Information
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Patent Application
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20030051270
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Publication Number
20030051270
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Date Filed
March 27, 200124 years ago
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Date Published
March 13, 200322 years ago
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CPC
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US Classifications
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International Classifications
- A61K048/00
- C07H021/02
- C07H021/04
Abstract
Presented are methods and compositions for targeted chromosomal genomic alterations using modified single-stranded oligonucleotides. The oligonucleotides of the invention have at least one modified nuclease-resistant terminal region comprising phosphorothioate linkages, LNA analogs or 2′-O-Me base analogs.
Description
FIELD OF THE INVENTION
[0001] The technical field of the invention is oligonucleotide-directed repair or alteration of genetic information using novel chemically modified oligonucleotides. Such genetic information is preferably from a eukaryotic organism, i.e. a plant, animal or fungus.
BACKGROUND OF THE INVENTION
[0002] A number of methods have been developed specifically to alter the sequence of an isolated DNA in addition to methods to alter directly the genomic information of various plants, fungi and animals, including humans (“gene therapy”). The latter methods generally include the use of viral or plasmid vectors carrying nucleic acid sequences encoding partial or complete portions of a particular protein which is expressed in a cell or tissue to effect the alteration. The expression of the particular protein then results in the desired phenotype. For example, retroviral vectors containing a transgenic DNA sequence allowing for the production of a normal CFTR protein when administered to defective cells are described in U.S. Pat. No. 5,240,846. Others have developed different “gene therapy vectors” which include, for example, portions of adenovirus (Ad) or adeno-associated virus (AAV), or other viruses. The virus portions used are often long terminal repeat sequences which are added to the ends of a transgene of choice along with other necessary control sequences which allow expression of the transgene. See U.S. Pat. Nos. 5,700,470 and 5,139,941. Similar methods have been developed for use in plants. See, for example, U.S. Pat. No. 4,459,355 which describes a method for transforming plants with a DNA vector and U.S. Pat. No. 5,188,642 which describes cloning or expression vectors containing a transgenic DNA sequence which when expressed in plants confers resistance to the herbicide glyphosate. The use of such transgene vectors in any eukaryotic organism adds one or more exogenous copies of a gene, which gene may be foreign to the host, in a usually random fashion at one or more integration sites of the organism's genome at some frequency. The gene which was originally present in the genome, which may be a normal allelic variant, mutated, defective, and/or functional, is retained in the genome of the host
[0003] These methods of gene correction are problematic in that complications which can compromise the health of the recipient, or even lead to death, may result. One such problem is that insertion of exogenous nucleic acid at random location(s) in the genome can have deleterious effects. Another problem with such systems includes the addition of unnecessary and unwanted genetic material to the genome of the recipient, including, for example, viral or other vector remnants, control sequences required to allow production of the transgene protein, and reporter genes or resistance markers. Such remnants and added sequences may have presently unrecognized consequences, for example, involving genetic rearrangements of the recipient genomes. Other problems associated with these types of traditional gene therapy methods include autoimmune suppression of cells expressing an inserted gene due to the presence of foreign antigens. Concerns have also been raised with consumption, especially by humans, of plants containing exogenous genetic material.
[0004] More recently, simpler systems involving poly- or oligo- nucleotides have been described for use in the alteration of genomic DNA. These chimeric RNA-DNA oligonucleotides, requiring contiguous RNA and DNA bases in a double-stranded molecule folded by complementarity into a double hairpin conformation, have been shown to effect single basepair or frameshift alterations, for example, for mutation or repair of plant or animal genomes. See, for example, WO 99/07865 and U.S. Pat. No. 5,565,350. In the chimeric RNA-DNA oligonucleotide, an uninterrupted stretch of DNA bases within the molecule is required for sequence alteration of the targeted genome while the obligate RNA residues are involved in complex stability. Due to the length, backbone composition, and structural configuration of these chimeric RNA-DNA molecules, they are expensive to synthesize and difficult to purify. Moreover, if the RNA-containing strand of the chimeric RNA-DNA oligonucleotide is designed so as to direct gene conversion, a series of mutagenic reactions resulting in nonspecific base alteration can result. Such a result compromises the utility of such a molecule in methods designed to alter the genomes of plants and animals, including in human gene therapy applications.
[0005] Alternatively, other oligo- or poly- nucleotides have been used which require a triplex forming, usually polypurine or polypyrimidine, structural domain which binds to a DNA helical duplex through Hoogsteen interactions between the major groove of the DNA duplex and the oligonucleotide. Such oligonucleotides may have an additional DNA reactive moiety, such as psoralen, covalently linked to the oligonucleotide. These reactive moieties function as effective intercalation agents, stabilize the formation of a triplex and can be mutagenic. Such agents may be required in order to stabilize the triplex forming domain of the oligonucleotide with the DNA double helix if the Hoogsteen interactions from the oligonucleotide/target base composition are insufficient. See, e.g., U.S. Pat. No. 5,422,251. The utility of these oligonucleotides for directing gene conversion is compromised by a high frequency of nonspecific base changes.
[0006] In more recent work, the domain for altering a genome is linked or tethered to the triplex forming domain of the bi-functional oligonucleotide, adding an additional linking or tethering functional domain to the oligonucleotide. See, e.g., Culver et al., Nature Biotechnology 17: 989-93 (1999). Such chimeric or triplex forming molecules have distinct structural requirements for each of the different domains of the complete poly- or oligo-nucleotide in order to effect the desired genomic alteration in either episomal or chromosomal targets.
[0007] Other genes, e.g. CFTR, have been targeted by homologous recombination using duplex fragments having several hundred basepairs. See, e.g., Kunzelmann et al., Gene Ther. 3:859-867 (1996). Early experiments to mutagenize an antibiotic resistance indicator gene by homologous recombination used an unmodified DNA oligonucleotide with no functional domains other than a region of complementary sequence to the target. See Campbell et al., New Biologist 1: 223-227 (1989). These experiments required large concentrations of the oligonucleotide, exhibited a very low frequency of episomal modification of a targeted exogenous plasmid gene not normally found in the cell and have not been reproduced. However, as shown in the examples herein, we have observed that an unmodified DNA oligonucleotide can convert a base at low frequency which is detectable using the assay systems described herein.
[0008] Artificial chromosomes can be useful for the screening purposed identified herein. These molecules are man-made linear or circular DNA molecules constructed from essential cis-acting DNA sequence elements that are responsible for the proper replication and partitioning of natural chromosomes (Murray et al., 1983). The essential elements are: (1) Autonomous Replication Sequences (ARS), (2) Centromeres, and (3) Telomeres.
[0009] Yeast artificial chromosomes (YACs) allow large genomic DNA to be modified and used for generating transgenic animals [Burke et al., Science 236:806; Peterson et al., Trends Genet. 13:61 (1997); Choi, et al., Nat Genet., 4:117-223 (1993), Davies, et al., Biotechnology 11:911-914 (1993), Matsuura, et al., Hum. Mol. Genet., 5:451-459 (1996), Peterson et al., Proc. Natl. Acad. Sci., 93:6605-6609 (1996); and Schedl, et al., Cell, 86:71-82 (1996)]. Other vectors also have been developed for the cloning of large segments of mammalian DNA, including cosmids, and bacteriophage P1 [Sternberg et al., Proc. Natl. Acad. Sci. U.S.A., 87:103-107 (1990)]. YACs have certain advantages over these alternative large capacity cloning vectors [Burke et al., Science, 236:806-812 (1987)]. The maximum insert size is 35-30 kb for cosmids, and 100 kb for bacteriophage P1, both of which are much smaller than the maximal insert for a YAC.
[0010] An alternative to YACs are E. coli based cloning systems based on the E. coli fertility factor that have been developed to construct large genomic DNA insert libraries. They are bacterial artificial chromosomes (BACs) and P-1 derived artificial chromosomes (PACs) [Mejia et al., Genome Res. 7:179-186 (1997); Shizuya et al., Proc. Natl. Acad. Sci. 89:8794-8797 (1992); loannou et al., Nat Genet., 6:84-89 (1994); Hosoda et al., Nucleic Acids Res. 18:3863 (1990)]. BACs are based on the E. coli fertility plasmid (F factor); and PACs are based on the bacteriophage P1. These vectors propagate at a very low copy number (1-2 per cell) enabling genomic inserts up to 300 kb in size to be stably maintained in recombination deficient hosts. Furthermore, the PACs and BACs are circular DNA molecules that are readily isolated from the host genomic background by classical alkaline lysis [Birnboim et al., Nucleic Acids Res. 7:1513-1523 (1979].
[0011] Oligonucleotides designed for use in the alteration of genetic information are significantly different from oligonucleotides designed for antisense approaches. For example, antisense oligonucleotides are perfectly complementary to and bind an mRNA strand in order to modify expression of a targeted mRNA and are used at high concentration. As a consequence, they are unable to produce a gene conversion event by either mutagenesis or repair of a defect in the chromosomal DNA of a host genome. Furthermore, the backbone chemical composition used in most oligonucleotides designed for use in antisense approaches renders them inactive as substrates for homologous pairing or mismatch repair enzymes and the high concentrations of oligonucleotide required for antisense applications can be toxic with some types of nucleotide modifications. In addition, antisense oligonucleotides must be complementary to the mRNA and therefore, may not be complementary to the other DNA strand or to genomic sequences that span the junction between intron sequence and exon sequence.
[0012] A need exists for simple, inexpensive oligonucleotides capable of producing targeted alteration of genetic material such as those described herein as well as methods to identify optimal oligonucleotides that accurately and efficiently alter target DNA.
SUMMARY OF THE INVENTION
[0013] Novel, modified single-stranded nucleic acid molecules that direct gene alteration in plants, fungi and animals are identified and the efficiency of alteration is analyzed both in vitro using a cell-free extract assay and in vivo using a yeast cell system. The alteration in an oligonucleotide of the invention may comprise an insertion, deletion, substitution, as well as any combination of these. Site specific alteration of DNA is not only useful for studying function of proteins in vivo, but it is also useful for creating animal models for human disease, and in gene therapy. As described herein, oligonucleotides of the invention target directed specific gene alterations in genomic double-stranded DNA cells. The target DNA can be normal, cellular chromosomal DNA, extrachromosomal DNA present in cells in different forms including, e.g., mammalian artificial chromosomes (MACs), PACs from P-1 vectors, yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), plant artificial chromosomes (PLACs), as well as episomal DNA, including episomal DNA from an exogenous source such as a plasmid or recombinant vector. Many of these artificial chromosome constructs containing human DNA can be obtained from a variety of sources, including, e.g., the Whitehead Institute, and are described, e.g., in Cohen et al., Nature 336:698-701 (1993) and Chumakov, et al., Nature 377:174-297 (1995). The target DNA may be transcriptionally silent or active. In a preferred embodiment, the target DNA to be altered is the non-transcribed strand of a genomic DNA duplex.
[0014] The low efficiency of gene alteration obtained using unmodified DNA oligonucleotides is believed to be largely the result of degradation by nucleases present in the reaction mixture or the target cell. Although different modifications are known to have different effects on the nuclease resistance of oligonucleotides or stability of duplexes formed by such oligonucleotides (see, e.g., Koshkin et al., J. Am. Chem. Soc., 120:13252-3), we have found that it is not possible to predict which of any particular known modification would be most useful for any given alteration event, including for the construction of gene conversion oligonucleotides, because of the interaction of different as yet unidentified proteins during the gene alteration event Herein, a variety of nucleic acid analogs have been developed that increase the nuclease resistance of oligonucleotides that contain them, including, e.g., nucleotides containing phosphorothioate linkages or 2′-O-methyl analogs. We recently discovered that single-stranded DNA oligonucleotides modified to contain 2′-O-methyl RNA nucleotides or phosphorothioate linkages can enable specific alteration of genetic information at a higher level than either unmodified single-stranded DNA or a chimeric RNA/DNA molecule. See priority applications incorporated herein in their entirety; see also Gamper et al., Nucleic Acids Research 28: 4332-4339 (2000). We also found that additional nucleic acid analogs which increase the nuclease resistance of oligonucleotides that contain them, including, e.g., “locked nucleic acids” or “LNAs”, xylo-LNAs and L-ribo-LNAs; see, for example, Wengel & Nielsen, WO 99/14226; Wengel, WO 00/56748 and Wengel, WO 00/66604; also allow specific targeted alteration of genetic information.
[0015] The assay allows for determining the optimum length of the oligonucleotide, optimum sequence of the oligonucleotide, optimum position of the mismatched base or bases, optimum chemical modification or modifications, optimum strand targeted for identifying and selecting the most efficient oligonucleotide for a particular gene alteration event by comparing to a control oligonucleotide. Control oligonucleotides may include a chimeric RNA-DNA double hairpin oligonucleotide directing the same gene alteration event, an oligonucleotide that matches its target completely, an oligonucleotide in which all linkages are phosphorothiolated, an oligonucleotide fully substituted with 2′-O-methyl analogs or an RNA oligonucleotide. Such control oligonucleotides either fail to direct a targeted alteration or do so at a lower efficiency as compared to the oligonucleotides of the invention. The assay further allows for determining the optimum position of a gene alteration event within an oligonucleotide, optimum concentration of the selected oligonucleotide for maximum alteration efficiency by systematically testing a range of concentrations, as well as optimization of either the source of cell extract by testing different organisms or strains, or testing cells derived from different organisms or strains, or cell lines. Using a series of single-stranded oligonucleotides, comprising all RNA or DNA residues and various mixtures of the two, several new structures are identified as viable molecules in nucleotide conversion to direct or repair a genomic mutagenic event When extracts from mammalian, plant and fungal cells are used and are analyzed using a genetic readout assay in bacteria, single-stranded oligonucleotides having one of several modifications are found to be more active than a control RNA-DNA double hairpin chimera structure when evaluated using an In vitro gene repair assay. Similar results are also observed in vivo using yeast, mammalian, rodent, monkey, human and embryonic cells, including stem cells. Molecules containing various lengths of modified bases were found to possess greater activity than unmodified single-stranded DNA molecules.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention provides oligonucleotides having chemically modified, nuclease resistant residues, preferably at or near the termini of the oligonucleotides, and methods for their identification and use in targeted alteration of genetic material, including gene mutation, targeted gene repair and gene knockout. The oligonucleotides are preferably used for mismatch repair or alteration by changing at least one nucleic acid base, or for frameshift repair or alteration by addition or deletion of at least one nucleic acid base. The oligonucleotides of the invention direct any such alteration, including gene correction, gene repair or gene mutation and can be used, for example, to introduce a polymorphism or haplotype or to eliminate (“knockout”) a particular protein activity.
[0017] The oligonucleotides of the invention are designed as substrates for homologous pairing and repair enzymes and as such have a unique backbone composition that differs from chimeric RNA-DNA double hairpin oligonucleotides, antisense oligonucleotides, and/or other poly- or oligonucleotides used for altering genomic DNA, such as triplex forming oligonucleotides. The single-stranded oligonucleotides described herein are inexpensive to synthesize and easy to purify. In side-by-side comparisons, an optimized single-stranded oligonucleotide comprising modified residues as described herein is significantly more efficient than a chimeric RNA-DNA double hairpin oligonucleotide in directing a base substitution or frameshift mutation in a cell-free extract assay.
[0018] We have discovered that single-stranded oligonucleotides having a DNA domain surrounding the targeted base, with the domain preferably central to the poly- or oligo-nucleotide, and having at least one modified end, preferably at the 3′ terminal region are able to alter a target genetic sequence and with an efficiency that is higher than chimeric RNA-DNA double hairpin oligonucleotides disclosed in U.S. Pat. No. 5,565,350. Oligonucleotides of the invention can efficiently be used to introduce targeted alterations in a genetic sequence of DNA in the presence of human, animal, plant, fungal (including yeast) proteins and in cultured cells of human liver, lung, colon, cervix, kidney, epethelium and cancer cells and in monkey, hamster, rat and mouse cells of different types, as well as embryonic stem cells. Cells for use in the invention include, e.g., fungi including S. cerevisiae, Ustillago maydis and Candida albicans, mammalian, mouse, hamster, rat, monkey, human and embryonic cells including stem cells. The DNA domain is preferably fully complementary to one strand of the gene target, except for the mismatch base or bases responsible for the gene alteration or conversion events. On either side of the preferably central DNA domain, the contiguous bases may be either RNA bases or, preferably, are primarily DNA bases. The central DNA domain is generally at least 8 nucleotides in length. The base(s) targeted for alteration in the most preferred embodiments are at least about 8, 9 or 10 bases from one end of the oligonucleotide.
[0019] According to certain embodiments, the termini of the oligonucleotides of the present invention comprise phosphorothioate modifications, LNA backbone modifications, or 2′-O-methyl base analogs, or any combination of these modifications. Oligonucleotides comprising 2′-O-methyl or LNA analogs are a mixed DNA/RNA polymer. These oligonucleotides are, however, single-stranded and are not designed to form a stable internal duplex structure within the oligonucleotide. The efficiency of gene alteration is surprisingly increased with oligonucleotides having internal complementary sequence comprising phosphorothioate modified bases as compared to 2′-O-methyl modifications. This result indicates that specific chemical interactions are involved between the converting oligonucleotide and the proteins involved in the conversion. The effect of other such chemical interactions to produce nuclease resistant termini using modifications other than LNA, phosphorothioate linkages, or 2′-O-methyl analog incorporation into an oligonucleotide can not yet be predicted because the proteins involved in the alteration process and their particular chemical interaction with the oligonucleotide substituents are not yet known and cannot be predicted.
[0020] In the examples, correcting oligonucleotides of defined sequence are provided for correction of genes mutated in human diseases. In the tables of these examples, the oligonucleotides of the invention are not limited to the particular sequences disclosed. The oligonucleotides of the invention include extensions of the appropriate sequence of the longer 120 base oligonucleotides which can be added base by base to the smallest disclosed oligonucleotides of 17 bases. Thus the oligonucleotides of the invention include for each correcting change, oligonucleotides of length 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 with further single-nucleotide additions up to the longest sequence disclosed. Moreover, the oligonucleotides of the invention do not require a symmetrical extension on either side of the central DNA domain. Similarly, the oligonucleotides of the invention as disclosed in the various tables for correction of human diseases contain phosphorothioate linkages, 2′-O-methyl analogs or LNAs or any combination of these modifications just as the assay oligonucleotides do.
[0021] The present invention, however, is not limited to oligonucleotides that contain any particular nuclease resistant modification. Oligonucleotides of the invention may be altered with any combination of additional LNAs, phosphorothioate linkages or 2′-O-methyl analogs to maximize conversion efficiency. For oligonucleotides of the invention that are longer than about 17 to about 25 bases in length, internal as well as terminal region segments of the backbone may be altered. Alternatively, simple fold-back structures at each end of a oligonucleotide or appended end groups may be used in addition to a modified backbone for conferring additional nuclease resistance.
[0022] The different oligonucleotides of the present invention preferably contain more than one of the aforementioned backbone modifications at each end. In some embodiments, the backbone modifications are adjacent to one another. However, the optimal number and placement of backbone modifications for any individual oligonucleotide will vary with the length of the oligonucleotide and the particular type of backbone modification(s) that are used. If constructs of identical sequence having phosphorothioate linkages are compared, 2, 3, 4, 5, or 6 phosphorothioate linkages at each end are preferred. If constructs of identical sequence having 2′-O-methyl base analogs are compared, 1, 2, 3 or 4 analogs are preferred. The optimal number and type of backbone modifications for any particular oligonucleotide useful for altering target DNA may be determined empirically by comparing the alteration efficiency of the oligonucleotide comprising any combination of the modifications to a control molecule of comparable sequence using any of the assays described herein. The optimal position(s) for oligonucleotide modifications for a maximally efficient altering oligonucleotide can be determined by testing the various modifications as compared to control molecule of comparable sequence in one of the assays disclosed herein. In such assays, a control molecule includes, e.g., a completely 2′-O-methyl substituted molecule, a completely complementary oligonucleotide, or a chimeric RNA-DNA double hairpin.
[0023] Increasing the number of phosphorothioate linkages, LNAs or 2′-O-methyl bases beyond the preferred number generally decreases the gene repair activity of a 25 nucleotide long oligonucleotide. Based on analysis of the concentration of oligonucleotide present in the extract after different time periods of incubation, it is believed that the terminal modifications impart nuclease resistance to the oligonucleotide thereby allowing it to survive within the cellular environment However, this may not be the only possible mechanism by which such modifications confer greater efficiency of conversion. For example, as disclosed herein, certain modifications to oligonucleotides confer a greater improvement to the efficiency of conversion than other modifications.
[0024] Efficiency of conversion is defined herein as the percentage of recovered substate molecules that have undergone a conversion event Depending on the nature of the target genetic material, e.g. the genome of a cell, efficiency could be represented as the proportion of cells or clones containing an extrachromosomal element that exhibit a particular phenotype. Alternatively, representative samples of the target genetic material can be sequenced to determine the percentage that have acquired the desire change. The oligonucleotides of the invention in different embodiments can alter DNA one, two, three, four, five, six, seven, eight, nine, ten, twelve, fifteen, twenty, thirty, and fifty or more fold more than control oligonucleotides. Such control oligonucleotides are oligonucleotides with fully phosphorothiolated linkages, oligonucleotides that are fully substituted with 2′-O-methyl analogs, a perfectly matched oligonucleotide that is fully complementary to a target sequence or a chimeric DNA-RNA double hairpin oligonucleotide such as disclosed in U.S. Pat. No. 5,565,350.
[0025] In addition, for a given oligonucleotide length, additional modifications interfere with the ability of the oligonucleotide to act in concert with the cellular recombination or repair enzyme machinery which is necessary and required to mediate a targeted substitution, addition or deletion event in DNA. For example, fully phosphorothiolated or fully 2-O-methylated molecules are inefficient in targeted gene alteration.
[0026] The oligonucleotides of the invention as optimized for the purpose of targeted alteration of genetic material, including gene knockout or repair, are different in structure from antisense oligonucleotides that may possess a similar mixed chemical composition backbone. The oligonucleotides of the invention differ from such antisense oligonucleotides in chemical composition, structure, sequence, and in their ability to alter genomic DNA. Significantly, antisense oligonucleotides fail to direct targeted gene alteration. The oligonucleotides of the invention may target either the Watson or the Crick strand of DNA and can include any component of the genome including, for example, intron and exon sequences. The preferred embodiment of the invention is a modified oligonucleotide that binds to the non-transcribed strand of a genomic DNA duplex. In other words, the preferred oligonucleotides of the invention target the sense strand of the DNA, i.e. the oligonucleotides of the invention are complementary to the non-transcribed strand of the target duplex DNA. The sequence of the non-transcribed strand of a DNA duplex is found in the mRNA produced from that duplex, given that mRNA uses uracil-containing nucleotides in place of thymine-containing nucleotides.
[0027] Moreover, the initial observation that single-stranded oligonucleotides comprising these modifications and lacking any particular triplex forming domain have reproducibly enhanced gene repair activity in a variety of assay systems as compared to a chimeric RNA-DNA double-stranded hairpin control or single-stranded oligonucleotides comprising other backbone modifications was surprising. The single-stranded molecules of the invention totally lack the complementary RNA binding structure that stabilizes a normal chimeric double-stranded hairpin of the type disclosed in U.S. Pat. No. 5,565,350 yet is more effective in producing targeted base conversion as compared to such a chimeric RNA-DNA double-stranded hairpin. In addition, the molecules of the invention lack any particular triplex forming domain involved in Hoogsteen interactions with the DNA double helix and required by other known oligonucleotides in other oligonucleotide dependant gene conversion systems. Although the lack of these functional domains was expected to decrease the efficiency of an alteration in a sequence, just the opposite occurs: the efficiency of sequence alteration using the modified oligonucleotides of the invention is higher than the efficiency of sequence alteration using a chimeric RNA-DNA hairpin targeting the same sequence alteration. Moreover, the efficiency of sequence alteration or gene conversion directed by an unmodified oligonucleotide is many times lower as compared to a control chimeric RNA-DNA molecule or the modified oligonucleotides of the invention targeting the same sequence alteration. Similarly, molecules containing at least 3 2′-O-methyl base analogs are about four to five fold less efficient as compared to an oligonucleotide having the same number of phosphorothioate linkages.
[0028] The oligonucleotides of the present invention for alteration of a single base are about 17 to about 121 nucleotides in length, preferably about 17 to about 74 nucleotides in length. Most preferably, however, the oligonucleotides of the present invention are at least about 25 bases in length, unless there are self-dimerization structures within the oligonucleotide. If the oligonucleotide has such an unfavorable structure, lengths longer than 35 bases are preferred. Oligonucleotides with modified ends both shorter and longer than certain of the exemplified, modified oligonucleotides herein function as gene repair or gene knockout agents and are within the scope of the present invention.
[0029] Once an oligomer is chosen, it can be tested for its tendency to self-dimerize, since self-dimerization may result in reduced efficiency of alteration of genetic information. Checking for self-dimerizaton tendency can be accomplished manually or, more preferably, by using a software program. One such program is Oligo Analyzer 2.0, available through Integrated DNA Technologies (Coralville, Iowa 52241) (http://www.idtdna.com); this program is available for use on the world wide web at http://www.idtdna.com/program/oligoanalyzer/oligoanalyzer.asp.
[0030] For each oligonucleotide sequence input into the program, Oligo Analyzer 2.0 reports possible self-dimerized duplex forms, which are usually only partially duplexed, along with the free energy change associated with such self-dimerization. Delta G-values that are negative and large in magnitude, indicating strong self-dimerization potential, are automatically flagged by the software as “bad”. Another software program that analyzes oligomers for pair dimer formation is Primer Select from DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715, Phone: (608) 258-7420 (http://www.dnastar.com/products/PrimerSelect.html). If the sequence is subject to significant self-dimerization, the addition of further sequence flanking the “repair” nucleotide can improve gene correction frequency.
[0031] Generally, the oligonucleotides of the present invention are identical in sequence to one strand of the target DNA, which can be either strand of the target DNA, with the exception of one or more targeted bases positioned within the DNA domain of the oligonucleotide, and preferably toward the middle between the modified terminal regions. Preferably, the difference in sequence of the oligonucleotide as compared to the targeted genomic DNA is located at about the middle of the oligonucleotide sequence. In a preferred embodiment, the oligonucleotides of the invention are complementary to the non-transcribed strand of a duplex. In other words, the preferred oligonucleotides target the sense strand of the DNA, i.e. the oligonucleotides of the invention are preferably complementary to the strand of the target DNA the sequence of which is found in the mRNA.
[0032] The oligonucleotides of the invention can include more than a single base change. In an oligonucleotide that is about a 70-mer, with at least one modified residue incorporated on the ends, as disclosed herein, multiple bases can be simultaneously targeted for change. The target bases may be up to 27 nucleotides apart and may not be changed together in all resultant plasmids in all cases. There is a frequency distribution such that the closer the target bases are to each other in the central DNA domain within the oligonucleotides of the invention, the higher the frequency of change in a given cell. Target bases only two nucleotides apart are changed together in every case that has been analyzed. The farther apart the two target bases are, the less frequent the simultaneous change. Thus, oligonucleotides of the invention may be used to repair or alter multiple bases rather than just one single base. For example, in a 74-mer oligonucleotide having a central base targeted for change, a base change event up to about 27 nucleotides away can also be effected. The positions of the altering bases within the oligonucleotide can be optimized using any one of the assays described herein. Preferably, the altering bases are at least about 8 nucleotides from one end of the oligonucleotide.
[0033] The oligonucleotides of the present invention can be introduced into cells by any suitable means. According to certain preferred embodiments, the modified oligonucleotides may be used alone. Suitable means, however, include the use of polycations, cationic lipids, liposomes, polyethylenimine (PEI), electroporation, biolistics, microinjection and other methods known in the art to facilitate cellular uptake. According to certain preferred embodiments of the present invention, the isolated cells are treated in culture according to the methods of the invention, to mutate or repair a target gene. Modified cells may then be reintroduced into the organism as, for example, in bone marrow having a targeted gene. Alternatively, modified cells may be used to regenerate the whole organism as, for example, in a plant having a desired targeted genomic change. In other instances, targeted genomic alteration, including repair or mutagenesis, may take place in vivo following direct administration of the modified, single-stranded oligonucleotides of the invention to a subject.
[0034] The single-stranded, modified oligonucleotides of the present invention have numerous applications as gene repair, gene modification, or gene knockout agents. Such oligonucleotides may be advantageously used, for example, to introduce or correct multiple point mutations. Each mutation leads to the addition, deletion or substitution of at least one base pair. The methods of the present invention offer distinct advantages over other methods of altering the genetic makeup of an organism, in that only the individually targeted bases are altered. No additional foreign DNA sequences are added to the genetic complement of the organism. Such agents may, for example, be used to develop plants or animals with improved traits by rationally changing the sequence of selected genes in cultured cells. Modified cells are then cloned into whole plants or animals having the altered gene. See, e.g., U.S. Pat. No. 6,046,380 and U.S. Pat. No. 5,905,185 incorporated hererin by reference. Such plants or animals produced using the compositions of the invention lack additional undesirable selectable markers or other foreign DNA sequences. Targeted base pair substitution or frameshift mutations introduced by an oligo-nucleotide in the presence of a cell-free extract also provides a way to modify the sequence of extrachromosomal elements, including, for example, plasmids, cosmids and artificial chromosomes. The oligonucleotides of the invention also simplify the production of transgenic animals having particular modified or inactivated genes. Altered animal or plant model systems such as those produced using the methods and oligonucleotides of the invention are invaluable in determining the function of a gene and in evaluating drugs. The oligonucleotides and methods of the present invention may also be used for gene therapy to correct mutations causative of human diseases.
[0035] The purified oligonucleotide compositions may be formulated in accordance with routine procedures as a pharmaceutical composition adapted for bathing cells in culture, for microinjection into cells in culture, and for intravenous administration to human beings or animals. Typically, compositions for cellular administration or for intravenous administration into animals, including humans, are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients will be supplied either separately or mixed together in unit dosage form, for example, as a dry, lyophilized powder or water-free concentrate. The composition may be stored in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent in activity units. Where the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade “water for injection” or saline. Where the composition is to be administered by injection, an ampule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
[0036] Pharmaceutical compositions of this invention comprise the compounds of the present invention and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable ingredient, excipient, carrier, adjuvant or vehicle.
[0037] The oliqonucleotides of the invention are preferably administered to the subject in the form of an injectable composition. The composition is preferably administered parenterally, meaning intravenously, intraarterially, intrathecally, interstitially or intracavitarilly. Pharmaceutical compositions of this invention can be administered to mammals including humans in a manner similar to other diagnostic or therapeutic agents. The dosage to be administered, and the mode of administration will depend on a variety of factors including age, weight, sex, condition of the subject and genetic factors, and will ultimately be decided by medical personnel subsequent to experimental determinations of varying dosage as described herein. In general, dosage required for correction and therapeutic efficacy will range from about 0.001 to 50,000 μg/kg, preferably between 1 to 250 μg/kg of host cell or body mass, and most preferably at a concentration of between 30 and 60 micromolar.
[0038] For cell administration, direct injection into the nucleus, biolistic bombardment, electroporation, liposome transfer and calcium phosphate precipitation may be used. In yeast, lithium acetate or spheroplasttransformation may also be used. In a preferred method, the administration is performed with a liposomal transfer compound, e.g., DOTAP (Boehringer-Mannheim) or an equivalent such as lipofectin. The amount of the oligonucleotide used is about 500 nanograms in 3 micrograms of DOTAP per 100,000 cells. For electroporation, between 20 and 2000 nanograms of oligonucleotide per million cells to be electroporated is an appropriate range of dosages which can be increased to improve efficiency of genetic alteration upon review of the appropriate sequence according to the methods described herein.
[0039] Another aspect of the invention is a kit comprising at least one oligonucleotide of the invention. The kit may comprise an addition reagent or article of manufacture. The additional reagent or article of manufacture may comprise a cell extract, a cell, or a plasmid, such as one of those disclosed in the Figures herein, for use in an assay of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040]
FIG. 1. Flow diagram for the generation of modified single-stranded oligonucleotides. The upper strands of chimeric oligonucleotides I and II are separated into pathways resulting in the generation of single-stranded oligonucleotides that contain (A) 2′-O-methyl RNA nucleotides or (B) phosphorothioate linkages. Fold changes in repair activity for correction of kans in the HUH7 cell-free extract are presented in parenthesis. HUH7 cells are described in Nakabayashi et al., Cancer Research 42: 3858-3863 (1982). Each single-stranded oligonucleotide is 25 bases in length and contains a G residue mismatched to the complementary sequence of the kans gene. The numbers 3, 6, 8, 10,12 and 12.5 respectively indicate how many phosphorothioate linkages (S) or 2′-O-methyl RNA nucleotides (R) are at each end of the molecule. Hence oligo 12S/25G contains an all phosphorothioate backbone, displayed as a dotted line. Smooth lines indicate DNA residues, wavy lines indicate 2′-O-methyl RNA residues and the carat indicates the mismatched base site (G). FIG. 1 (C) provides a schematic plasmid indicating the sequence of the kan chimeric double-stranded hairpin oligonucleotide (left) and the sequence the tet chimeric double-stranded hairpin oligonucleotide used in other experiments. FIG. 1 (D) provides a flow chart of a kan experiment in which a chimeric double-stranded hairpin oligonucleotide is used.
[0041]
FIG. 2. Genetic readout system for correction of a point mutation in plasmid pKsm4021. A mutant kanamycin gene harbored in plasmid pKsm4021 is the target for correction by oligonucleotides. The mutant G is converted to a C by the action of the oligo. Corrected plasmids confer resistance to kanamycin in E. coli (DH10B) after electroporation leading to the genetic readout and colony counts.
[0042]
FIG. 3: Target plasmid and sequence correction of a frameshift mutation by chimeric and single-stranded oligonucleotides. (A) Plasmid pTsΔ208 contains a single base deletion mutation at position 208 rendering it unable to confer tet resistance. The target sequence presented below indicates the insertion of a T directed by the oligonucleotides to re-establish the resistant phenotype. (B) DNA sequence confirming base insertion directed by Tet 3S/25G; the yellow highlight indicates the position of frameshift repair.
[0043]
FIG. 4. DNA sequences of representative kanr colonies. Confirmation of sequence alteration directed by the indicated molecule is presented along with a table outlining codon distribution. Note that 10S/25G and 12S/25G elicit both mixed and unfaithful gene repair. The number of clones sequenced is listed in parentheses next to the designation for the single-stranded oligonucleotide. A plus (+) symbol indicates the codon identified while a figure after the (+) symbol indicates the number of colonies with a particular sequence. TAC/TAG indicates a mixed peak. Representative DNA sequences are presented below the table with yellow highlighting altered residues.
[0044]
FIG. 5. Gene correction in HeLa cells. Representative oligonucleotides of the invention are co-transfected with the pCMVneo(−)FIAsH plasmid (shown in FIG. 9) into HeLa cells. Ligand is diffused into cells after co-transfection of plasmid and oligonucleotides. Green fluorescence indicates gene correction of the mutation in the antibiotic resistance gene. Correction of the mutation results in the expression of a fusion protein that carries a marker ligand binding site and when the fusion protein binds the ligand, a green fluorescence is emitted. The ligand is produced by Aurora Biosciences and can readily diffuse into cells enabling a measurement of corrected protein function; the protein must bind the ligand directly to induce fluorescence. Hence cells bearing the corrected plasmid gene appear green while “uncorrected” cells remain colorless.
[0045]
FIG. 6. Z-series imaging of corrected cells. Serial cross-sections of the HeLa cell represented in FIG. 5 are produced by Zeiss 510 LSM confocal microscope revealing that the fusion protein is contained within the cell.
[0046]
FIG. 7. Hygromycin-eGFP target plasmids. (A) Plasmid pAURHYG(ins)GFP contains a single base insertion mutation between nucleotides 136 and 137, at codon 46, of the Hygromycin B coding sequence (cds) which is transcribed from the constitutive ADHL promoter. The target sequence presented below indicates the deletion of an A and the substitution of a C for a T directed by the oligonucleotides to re-establish the resistant phenotype. (B) Plasmid pAURHYG(rep)GFP contains a base substitution mutation introducing a G at nucleotide 137, at codon 46, of the Hygromycin B coding sequence (cds). The target sequence presented below the diagram indicates the amino acid conservative replacement of G with C, restoring gene function.
[0047]
FIG. 8. Oligonucleotides for correction of hygromycin resistance gene. The sequence of the oligonucleotides used in experiments to assay correction of a hygromycin resistance gene are shown. DNA residues are shown in capital letters, RNA residues are shown in lowercase and nucleotides with a phosphorothioate backbone are capitalized and underlined.
[0048]
FIG. 9. pAURNeo(−)FIAsH plasmid. This figure describes the plasmid structure, target sequence, oligonucleotides, and the basis for detection of the gene alteration event by fluorescence.
[0049]
FIG. 10. pYESHyg(x)eGFP plasmid. This plasmid is a construct similar to the pAURHyg(x)eGFP construct shown in FIG. 7, except the promoter is the inducible GALL promoter. This promoter is inducible with galactose, leaky in the presence of raffinose, and repressed in the presence of dextrose.
[0050] The following examples are provided by way of illustration only, and are not intended to limit the scope of the invention disclosed herein.
Assay Method For Base Alteration And Preferred Oligonucleotide Selection
[0051] In this example, single-stranded and double-hairpin oligonucleotides with chimeric backbones (see FIG. 1 for structures (A and B) and sequences (C and D) of assay oligonucleotides) are used to correct a point mutation in the kanamycin gene of pKsm4021 (FIG. 2) or the tetracycline gene of pTsΔ208 (FIG. 3). All kan oligonucleotides share the same 25 base sequence surrounding the target base identified for change, just as all tet oligonucleotides do. The sequence is given in FIGS. 1C and 1D. Each plasmid contains a functional ampicillin gene. Kanamycin gene function is restored when a G at position 4021 is converted to a C (via a substitution mutation); tetracycline gene function is restored when a deletion at position 208 is replaced by a C (via frameshift mutation). A separate plasmid, pAURNeo(−)FIAsH (FIG. 9), bearing the kans gene is used in the cell culture experiments. This plasmid was constructed by inserting a synthetic expression cassette containing a neomycin phosphotransferase (kanamycin resistance) gene and an extended reading frame that encodes a receptor for the FIAsH ligand into the pAUR123 shuttle vector (Panvera Corp., Madison, Wis.). The resulting construct replicates in S. cerevisiae at low copy number, confers resistance to aureobasidinA and constitutively expresses either the Neo+/FIAsH fusion product (after alteration) or the truncated Neo-/FIAsH product (before alteration) from the ADH1 promoter. By extending the reading frame of this gene to code for a unique peptide sequence capable of binding a small ligand to form a fluorescent complex, restoration of expression by correction of the stop codon can be detected in real time using confocal microscopy. Additional constructs can be made to test additional gene alteration events.
[0052] We also construct three mammalian expression vectors, pHyg(rep)eGFP, pHyg(Δ)eGFP, pHyg(ins)eGFP, that contain a substitution mutation at nucleotide 137 of the hygromycin-B coding sequence. (rep) indicates a T137→G replacement, (Δ) represents a deletion of the G137 and (ins) represents an A insertion between nucleotides 136 and 137. All point mutations create a nonsense termination codon at residue 46. We use pHygEGFP plasmid (Invitrogen, Calif.) DNA as a template to introduce the mutations into the hygromycin-eGFP fusion gene by a two step site-directed mutagenesis PCR protocol. First, we generate overlapping 5′ and a 3′ amplicons surrounding the mutation site by PCR for each of the point mutation sites. A 215 bp 5′ amplicon for the (rep), (Δ) or (ins) was generated by polymerization from oligonucleotide primer HygEGFPf (5′-AATACGACTCACTATAGG-3′) to primer Hygrepr (5′GACCTATCCACGCCCTCC-3′), HygΔr (5′-GACTATCCACGCCCTCC-3′), or Hyginsr (5′-GACATTATCCACGCCCTCC-3′), respectively. We generate a 300 bp 3′ amplicon for the (rep), (Δ) or (ins) by polymerization from oligonucleotide primers Hygrepf (5′-CTGGGATAGGTCCTGCGG-3′), HygΔf (5′-CGTGGATAGTCCTGCGG-3′), Hyginsf (5′-CGTGGATMTGTCCTGCGG-3′), respectively to primer HygEGFPr (5′-AAATCACGCCATGTAGTG-3′). We mix 20 ng of each of the resultant 5′ and 3′ overlapping amplicon mutation sets and use the mixture as a template to amplify a 523 bp fragment of the Hygromycin gene spanning the Kpnl and Rsrll restriction endonuclease sites. We use the Expand PCR system (Roche) to generate all amplicons with 25 cycles of denaturing at 94° C. for 10 seconds, annealing at 55° C. for 20 seconds and elongation at 68° C. for 1 minute. We digest 10 μg of vector pHygEGFP and 5 μg of the resulting fragments for each mutation with Kpnl and Rsrll (NEB) and gel purify the fragment for enzymatic ligation. We ligate each mutated insert into pHygEGFP vector at 3:1 molar ration using T4 DNA ligase (Roche). We screen clones by restriction digest, confirm the mutation by Sanger dideoxy chain termination sequencing and purify the plasmid using a Qiagen maxiprep kit
[0053] Oligonucleotide synthesis and cells. Chimeric oligonucleotides and single-stranded oligonucleotides (including those with the indicated modifications) are synthesized using available phosphoramidites on controlled pore glass supports. After deprotection and detachment from the solid support, each oligonucleotide is gel-purified using, for example, procedures such as those described in Gamper et al., Biochem. 39, 5808-5816 (2000) and the concentrations determined spectrophotometrically (33 or 40 μg/ml per A260 unit of single-stranded or hairpin oligomer). HUH7 cells are grown in DMEM, 10% FBS, 2 mM glutamine, 0.5% pen/strep. The E. coli strain, DH10B, is obtained from Life Technologies (Gaithersburg, Md.); DH10B cells contain a mutation in the RECA gene (recA).
[0054] Cell-free extracts. We prepare cell-free extracts from HUH7 cells or other mammalian cells, as follows. We employ this protocol with essentially any mammalian cell including, for example, H1299 cells (human epithelial carcinoma, non-small cell lung cancer), C127I (immortal murine mammary epithelial cells), MEF (mouse embryonic fibroblasts), HEC-1-A (human uterine carcinoma), HCT15 (human colon cancer), HCT116 (human colon carcinoma), LoVo (human colon adenocarcinoma), and HeLa (human cervical carcinoma). We harvest approximately 2×108 cells. We then wash the cells immediately in cold hypotonic buffer (20 mM HEPES, pH7.5; 5 mM KCl; 1.5 mM MgCl2; 1 mM DTT) with 250 mM sucrose. We then resuspend the cells in cold hypotonic buffer without sucrose and after 15 minutes we lyse the cells with 25 strokes of a Dounce homogenizer using a tight fitting pestle. We incubate the lysed cells for 60 minutes on ice and centrifuge the sample for 15 minutes at 12000 xg. The cytoplasmic fraction is enriched with nuclear proteins due to the extended co-incubation of the fractions following cell breakage. We then immediately aliquote and freeze the supernatant at −80° C. We determine the protein concentration in the extract by the Bradford assay.
[0055] We also perform these experiments with cell-free extracts obtained from fungal cells, including, for example, S. cerevisiae (yeast), Ustilago maydis, and Candida albicans. For example, we grow yeast cells into log phase in 2L YPD medium for 3 days at 30° C. We then centrifuge the cultures at 5000 xg, resuspend the pellets in a 10% sucrose, 50 mM Tris, 1 mM EDTA lysis solution and freeze them on dry ice. After thawing, we add KCl, spermidine and lyticase to final concentrations of 0.25 mM, 5 mM and 0.1 mg/ml, respectively. We incubate the suspension on ice for 60 minutes, add PMSF and Triton ×100 to final concentrations of 0.1 mM and 0.1% and continue to incubate on ice for 20 minutes. We centrifuge the lysate at 3000 xg for 10 minutes to remove larger debris. We then remove the supernatant and clarify it by centrifuging at 30000 xg for 15 minutes. We then add glycerol to the clarified extract to a concentration of 10% (v/v) and freeze aliquots at −80° C. We determine the protein concentration of the extract by the Bradford assay.
[0056] Reaction mixtures of 50 μl are used, consisting of 10-30 μg protein of cell-free extract, which can be optionally substituted with purified proteins or enriched fractions, about 1.5 μg chimeric double-hairpin oligonucleotide or 0.55 μg single-stranded molecule (3S/25G or 6S/25G, see FIG. 1), and 1 μg of plasmid DNA (see FIGS. 2 and 3) in a reaction buffer of 20 mM Tris, pH 7.4,15 mM MgCl2, 0.4 mM DTT, and 1.0 mM ATP. Reactions are initiated with extract and incubated at 30° C. for 45 min. The reaction is stopped by placing the tubes on ice and then immediately deproteinized by two phenol/chloroform (1:1) extractions. Samples are then ethanol precipitated. The nucleic acid is pelleted at 15,000 r.p.m. at 4° C. for 30 min., is washed with 70% ethanol, resuspended in 50 μl H2O, and is stored at −20° C. 5 μl of plasmid from the resuspension (˜100 ng) was transfected in 20 μl of DH10B cells by electroporation (400 V, 300 μF, 4 kΩ) in a Cell-Porator apparatus (Life Technologies). After electroporation, cells are transferred to a 14 ml Falcon snap-cap tube with 2 ml SOC and shaken at 37° C. for 1 h. Enhancement of final kan colony counts is achieved by then adding 3 ml SOC with 10 μg/ml kanamycin and the cell suspension is shaken for a further 2 h at 37° C. Cells are then spun down at 3750×g and the pellet is resuspended in 500 μl, SOC. 200 μl is added undiluted to each of two kanamycin (50 μg/ml) agar plates and 200 μl of a 105 dilution is added to an ampicillin (100 μg/ml) plate. After overnight 37° C. incubation, bacterial colonies are counted using an Accu-count 1000 (Biologics). Gene conversion effectiveness is measured as the ratio of the average of the kan colonies on both plates per amp colonies multiplied by 10−5 to correct for the amp dilution.
[0057] The following procedure can also be used. 5 μl of resuspended reaction mixtures (total volume 50 μl) are used to transform 20 μl aliquots of electro-competent ΔH10B bacteria using a Cell-Porator apparatus (Life Technologies). The mixtures are allowed to recover in 1 ml SOC at 37° C. for 1 hour at which time 50 μg/ml kanamycin or 12 μg/ml tetracycline is added for an additional 3 hours. Prior to plating, the bacteria are pelleted and resuspended in 200 μl of SOC. 100 μl aliquots are plated onto kan or tet agar plates and 100 μl of a 10−4 dilution of the cultures are concurrently plated on agar plates containing 100 μg/ml of ampicillin. Plating is performed in triplicate using sterile Pyrex beads. Colony counts are determined by an Accu-count 1000 plate reader (Biologics). Each plate contains 200-500 ampicillin resistant colonies or 0-500 tetracycline or kanamycin resistant colonies. Resistant colonies are selected for plasmid extraction and DNA sequencing using an ABI Prism kit on an ABI 310 capillary sequencer (PE Biosystems).
[0058] Chimeric single-stranded oligonucleotides. In FIG. 1 the upper strands of chimeric oligonucleotides I and II are separated into pathways resulting in the generation of single-stranded oligonucleotides that contain (FIG. 1A) 2′-O-methyl RNA nucleotides or (FIG. 1 B) phosphorothioate linkages. Fold changes in repair activity for correction of kans in the HUH7 cell-free extract are presented in parenthesis. Each single-stranded oligonucleotide is 25 bases in length and contains a G residue mismatched to the complementary sequence of the kans gene.
[0059] Molecules bearing 3, 6, 8, 10 and 12 phosphorothioate linkages in the terminal regions at each end of a backbone with a total of 24 linkages (25 bases) are tested in the kans system. Alternatively, molecules bearing 2, 4, 5, 7, 9 and 11 in the terminal regions at each end are tested. The results of one such experiment, presented in Table 1 and FIG. 1B, illustrate an enhancement of correction activity directed by some of these modified structures. In this illustrative example, the most efficient molecules contained 3 or 6 phosphorothioate linkages at each end of the 25-mer; the activities are approximately equal (molecules IX and X with results of 3.09 and 3.7 respectively). A reduction in alteration activity may be observed as the number of modified linkages in the molecule is further increased. Interestingly, a single-strand molecule containing 24 phosphorothioate linkages is minimally active suggesting that this backbone modification when used throughout the molecule supports only a low level of targeted gene repair or alteration. Such a non-altering, completely modified molecule can provide a baseline control for determining efficiency of correction for a specific oligonucleotide molecule of known sequence in defining the optimum oligonucleotide for a particular alteration event.
[0060] The efficiency of gene repair directed by phosphorothioate-modified, single-stranded molecules, in a length dependent fashion, led us to examine the length of the RNA modification used in the original chimera as it relates to correction. Construct III represents the “RNA-containing” strand of chimera I and, as shown in Table 1 and FIG. 2A, it promotes inefficient gene repair. But, as shown in the same figure, reducing the RNA residues on each end from 10 to 3 increases the frequency of repair. At equal levels of modification, however, 25-mers with 2′-O-methyl ribonucleotides were less effective gene repair agents than the same oligomers with phosphorothioate linkages. These results reinforce the fact that an RNA containing oligonucleotide is not as effective in promoting gene repair or alteration as a modified DNA oligonucleotide.
[0061] Repair of the kanamycin mutation requires a G→C exchange. To confirm that the specific desired correction alteration was obtained, colonies selected at random from multiple experiments are processed and the isolated plasmid DNA is sequenced. As seen in FIG. 4, colonies generated through the action of the single-stranded molecules 3S/25G (IX), 6S/25G (X) and 8S/25G (XI) respectively contained plasmid molecules harboring the targeted base correction. While a few colonies appeared on plates derived from reaction mixtures containing 25-mers with 10 or 12 thioate linkages on both ends, the sequences of the plasmid molecules from these colonies contain nonspecific base changes. In these illustrative examples, the second base of the codon is changed (see FIG. 3). These results show that modified single-strands can direct gene repair, but that efficiency and specificity are reduced when the 25-mers contain 10 or more phosphorothioate linkages at each end.
[0062] In FIG. 1, the numbers 3, 6, 8, 10, 12 and 12.5 respectively indicate how many phosphorothioate linkages (S) or 2′-O-methyl RNA nucleotides (R) are at each end of the examplified molecule although other molecules with 2, 4, 5, 7, 9 and 11 modifications at each end can also be tested. Hence oligo 12S/25G represents a 25-mer oligonucleotide which contains 12 phosphorothioate linkages on each side of the central G target mismatch base producing a fully phosphorothioate linked backbone, displayed as a dotted line. The dots are merely representative of a linkage in the figure and do not depict the actual number of linkages of the oligonucleotide. Smooth lines indicate DNA residues, wavy lines indicate 2′-O-methyl RNA residues and the carat indicates the mismatched base site (G).
[0063] Correction of a mutant kanamycin gene in cultured mammalian cells. The experiments are performed using different mammalian cells, including, for example, 293 cells (transformed human primary kidney cells), HeLa cells (human cervical carcinoma), and H1299 (human epithelial carcinoma, non-small cell lung cancer). HeLa cells are grown at 37° C. and 5% CO2 in a humidified incubator to a density of 2×105 cells/ml in an 8 chamber slide (Lab-Tek). After replacing the regular DMEM with Optimem, the cells are co-transfected with 10 μg of plasmid pAURNeo(−)FIAsH and 5 μg of modified single-stranded oligonucleotide (3S/25G) that is previously complexed with 10 μg lipofectamine, according to the manufacturer's directions (Life Technologies). The cells are treated with the liposome-DNA-oligo mix for 6 hrs at 37° C. Treated cells are washed with PBS and fresh DMEM is added. After a 16-18 hr recovery period, the culture is assayed for gene repair. The same oligonucleotide used in the cell-free extract experiments is used to target transfected plasmid bearing the kans gene. Correction of the point mutation in this gene eliminates a stop codon and restores full expression. This expression can be detected by adding a small non-fluorescent ligand that bound to a C-C-R-E-C-C sequence in the genetically modified carboxy terminus of the kan protein, to produce a highly fluorescent complex (FIAsH system, Aurora Biosciences Corporation). Following a 60 min incubation at room temperature with the ligand (FIAsH-EDT2),cells expressing full length kan product acquire an intense green fluorescence detectable by fluorescence microscopy using a fluorescein filter set. Similar experiments are performed using the HygeGFP target as described in Example 2 with a variety of mammalian cells, including, for example, COS-1 and COS-7 cells (African green monkey), and CHO-K1 cells (Chinese hamster ovary). The experiments are also performed with PG12 cells (rat pheochromocytoma) and ES cells (human embryonic stem cells).
[0064] Summary of experimental results. Tables 1, 2 and 3 respectively provide data on the efficiency of gene repair directed by single-stranded oligonucleotides. Table 1 presents data using a cell-free extract from human liver cells (HUH7) to catalyze repair of the point mutation in plasmid pkansm4021 (see FIG. 1). Table 2 illustrates that the oligomers are not dependent on MSH2 or MSH3 for optimal gene repair activity. Table 3 illustrates data from the repair of a frameshift mutation (FIG. 3) in the tet gene contained in plasmid pTetA208. Table 4 illustrates data from repair of the pkansm4021 point mutation catalyzed by plant cell extracts prepared from canola and musa (banana). Colony numbers are presented as kanr or tetr and fold increases (single strand versus double hairpin) are presented for kanr in Table 1.
[0065]
FIG. 5A is a confocal picture of HeLa cells expressing the corrected fusion protein from an episomal target. Gene repair is accomplished by the action of a modified single-stranded oligonucleotide containing 3 phosphorothioate linkages at each end (3S/25G). FIG. 5B represents a “Z-series” of HeLa cells bearing the corrected fusion gene. This series sections the cells from bottom to top and illustrates that the fluorescent signal is “inside the cells”.
[0066] Results. In summary, we have designed a novel class of single-stranded oligonucleotides with backbone modifications at the termini and demonstrate gene repair/conversion activity in mammalian and plant cell-free extracts. We confirm that the all DNA strand of the RNA-DNA double-stranded double hairpin chimera is the active component in the process of gene repair. In some cases, the relative frequency of repair by the novel oligonucleotides of the invention is elevated approximately 3-4fold when compared to frequencies directed by chimeric RNA-DNA double hairpin oligonucleotides.
[0067] This strategy centers around the use of extracts from various sources to correct a mutation in a plasmid using a modified single-stranded or a chimeric RNA-DNA double hairpin oligonucleotide. A mutation is placed inside the coding region of a gene conferring antibiotic resistance in bacteria, here kanamycin or tetracycline. The appearance of resistance is measured by genetic readout in E. coli grown in the presence of the specified antibiotic. The importance of this system is that both phenotypic alteration and genetic inheritance can be measured. Plasmid pKsm4021 contains a mutation (TOG) at residue 4021 rendering it unable to confer antibiotic resistance in E. coli. This point mutation is targeted for repair by oligonucleotides designed to restore kanamycin resistance. To avoid concerns of plasmid contamination skewing the colony counts, the directed correction is from G→C rather than G→T (wild-type). After isolation, the plasmid is electroporated into the DH10B strain of E. coli, which contains inactive RecA protein. The number of kanamycin colonies is counted and normalized by ascertaining the number of ampicillin colonies, a process that controls for the influence of electroporation. The number of colonies generated from three to five independent reactions was averaged and is presented for each experiment. A fold increase number is recorded to aid in comparison.
[0068] The original RNA-DNA double hairpin chimera design, e.g., as disclosed in U.S. Pat. No. 5,565,350, consists of two hybridized regions of a single-stranded oligonucleotide folded into a double hairpin configuration. The double-stranded targeting region is made up of a 5 base pair DNA/DNA segment bracketed by 10 base pair RNA/DNA segments. The central base pair is mismatched to the corresponding base pair in the target gene. When a molecule of this design is used to correct the kans mutation, gene repair is observed (I in FIG. 1A). Chimera II (FIG. 1B) differs partly from chimera I in that only the DNA strand of the double hairpin is mismatched to the target sequence. When this chimera was used to correct the kans mutation, it was twice as active. In the same study, repair function could be further increased by making the targeting region of the chimera a continuous RNA/DNA hybrid.
[0069] Frame shift mutations are repaired. By using plasmid pTsΔ208, described in FIG. 1 (C) and FIG. 3, the capacity of the modified single-stranded molecules that showed activity in correcting a point mutation, can be tested for repair of a frameshift. To determine efficiency of correction of the mutation, a chimeric oligonucleotide (Tet I), which is designed to insert a T residue at position 208, is used. A modified single-stranded oligonucleotide (Tet IX) directs the insertion of a T residue at this same site. FIG. 3 illustrates the plasmid and target bases designated for change in the experiments. When all reaction components are present (extract, plasmid, oligomer), tetracycline resistant colonies appear. The colony count increases with the amount of oligonucleotide used up to a point beyond which the count falls off (Table 3). No colonies above background are observed in the absence of either extract or oligonucleotide, nor when a modified single-stranded molecule bearing perfect complementarity is used. FIG. 3 represents the sequence surrounding the target site and shows that a T residue is inserted at the correct site. We have isolated plasmids from fifteen colonies obtained in three independent experiments and each analyzed sequence revealed the same precise nucleotide insertion. These data suggest that the single-stranded molecules used initially for point mutation correction can also repair nucleotide deletions.
[0070] Comparison of phosphorothioate oligonucleotides to 2′-O-methyl substituted oligonucleotides. From a comparison of molecules VII and XI, it is apparent that gene repair is more subject to inhibition by RNA residues than by phosphorothioate linkages. Thus, even though both of these oligonucleotides contain an equal number of modifications to impart nuclease resistance, XI (with 16 phosphorothioate linkages) has good gene repair activity while VII (with 16 2′-O-methyl RNA residues) is inactive. Hence, the original chimeric double hairpin oligonucleotide enabled correction directed, in large part, by the strand containing a large region of contiguous DNA residues.
[0071] Oligonucleotides can target multiple nucleotide alterations within the same template. The ability of individual single-stranded oligonucleotides to correct multiple mutations in a single target template is tested using the plasmid pKsm4021 and the following single-stranded oligonucleotides modified with 3 phosphorothioate linkages at each end (indicated as underlined nucleotides): Oligo1 is a 25-mer with the sequence TTCGATAAGCCTATGCTGACCCGTG corrects the original mutation present in the kanamycin resistance gene of pKsm4021 as well as directing another alteration 2 basepairs away in the target sequence (both indicated in boldface); Oligo2 is a 70-mer with the 5′-end sequence TTCGGCTACGACTGGGCACAACAGACMTTGGC with the remaining nucleotides being completely complementary to the kanamycin resistance gene and also ending in 3 phosphorothioate linkages at the 3′ end. Oligo2 directs correction of the mutation in pKsm4021 as well as directing another alteration 21 basepairs away in the target sequence (both indicated in boldface).
[0072] We also use additional oligonucleotides to assay the ability of individual oligonucleotides to correct multiple mutations in the pKsM4021 plasmid. These include, for example, a second 25-mer that alters two nucleotides that are three nucleotides apart with the sequence 5′-TTGTGCCCAGTCGTATCCGAATAGC-3′; a 70-mer that alters two nucleotides that are 21 nucleotides apart with the sequence 5′-CATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAA TAGCCTCTCCACCCAAGCGGCCGGAGA-3′; and another 70-mer that alters two nucleotides that are 21 nucleotides apart with the sequence 5′-GCTGACAGCCGGAACACGGCGGCATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAATAGCCT-3′. The nucleotides in the oligonucleotides that direct alteration of the target sequence are underlined and in boldface. These oligonucleotides are modified in the same way as the other oligonucleotides of the invention.
[0073] We assay correction of the original mutation in pKsm4021 by monitoring kanamycin resistance (the second alterations which are directed by Oligo2 and Oligo3 are silent with respect to the kanamycin resistance phenotype). In addition, in experiments with Oligo2, we also monitor cleavage of the resulting plasmids using the restriction enzyme Tsp509I which cuts at a specific site present only when the second alteration has occurred (at ATT in Oligo2). We then sequence these clones to determine whether the additional, silent alteration has also been introduced. The results of an analysis are presented below:
1|
|
Oligo1 (25-mer)Oligo2 (70-mer)
|
|
Clones with both sites changed97
Clones with a single site changed02
Clones that were not changed41
|
[0074] Nuclease sensitivity of unmodified DNA oligonucleotide. Electrophoretic analysis of nucleic acid recovered from the cell-free extract reactions conducted here confirm that the unmodified single-stranded 25-mer did not survive incubation whereas greater than 90% of the terminally modified oligos did survive (as judged by photo-image analyses of agarose gels).
[0075] Plant extracts direct repair. The modified single-stranded constructs can be tested in plant cell extracts. We have observed gene alteration using extracts from multiple plant sources, including, for example, Arabidopsis, tobacco, banana, maize, soybean, canola, wheat, spinach as well as spinach chloroplast extract We prepare the extracts by grinding plant tissue or cultured cells under liquid nitrogen with a mortar and pestle. We extract 3 ml of the ground plant tissue with 1.5 ml of extraction buffer (20 mM HEPES, pH7.5; 5 mM Kcl; 1.5 mM MgCl2; 10 mM DTT; 10% [v/v] glycerol; and 1% [w/v] PVP). We then homogenize the samples with 15 strokes of a Dounce homogenizer. Following homogenization, we incubate the samples on ice for 1 hour and centrifuge at 3000 xg for 5 minutes to remove plant cell debris. We then determine the protein concentration in the supernatants (extracts) by Bradford assay. We dispense 100 μg (protein) aliquots of the extracts which we freeze in a dry ice-ethanol bath and store at −80° C.
[0076] We describe experiments using two sources here: a dicot (canola) and a monocot (banana, Musa acuminata cv. Rasthali). Each vector directs gene repair of the kanamycin mutation (Table 4); however, the level of correction is elevated 2-3 fold relative to the frequency observed with the chimeric oligonucleotide. These results are similar to those observed in the mammalian system wherein a significant improvement in gene repair occurred when modified single-stranded molecules were used.
[0077] Tables are attached hereto.
2TABLE I
|
|
Gene repair activity is directed by single-stranded oligonucleotides.
OligonucleotidePlasmidExtract (ug)kanr coloniesFold increase
|
IpKSm402110300
IpKSm4021204181.0x
IIpKSm402110537
IIpKSm4021207481.78x
IIIpKSm4021103
IIIpKSm40212050.01x
IVpKSm402110112
IVpKSm402120960.22x
VpKSm402110217
VpKSm4021203420.81x
VIpKSm4021106
VIpKSm402120390.093x
VIIpKSm4021100
VIIpKSm40212000x
VIIIpKSm4021103
VIIIpKSm40212050.01x
IXpKSm402110936
IXpKSm40212012953.09x
XpKSm4021101140
XpKSm40212015883.7x
XIpKSm402110480
XIpKSm4021206811.6x
XIIpKSm40211018
XIIpKSm402120250.059x
XIIIpKSm4021100
XIIIpKSm40212040.009x
—pKSm4021200
IpKSm4021—0
|
[0078] Plasmid pKsm4021 (1 μg), the indicated oligonucleotide (1.5 μg chimeric oligonucleotide or 0.55 μg single-stranded oligonucleotide; molar ratio of oligo to plasmid of 360 to 1) and either 10 or 20 μg of HUH7 cell-free extract were incubated 45 min at 37° C. Isolated plasmid DNA was electroporated into E. coli (strain DH10B) and the number of kanr colonies counted. The data represent the number of kanamycin resistant colonies per 106 ampicillin resistant colonies generated from the same reaction and is the average of three experiments (standard deviation usually less than +/−15%). Fold increase is defined relative to 418 kanr colonies (second reaction) and in all reactions was calculated using the 20 μg sample.
3TABLE II
|
|
Modified single-stranded oligomers are not dependent
on MSH2 or MSH3 for optimal gene repair activity.
A.OligonucleotidePlasmidExtractkanr colonies
|
IX (3S/25G)HUH7637
X (6S/25G)HUH7836
IXMEF2−/−781
XMEF2−/−676
IXMEF3−/−582
XMEF3−/−530
IXMEF+/+332
XMEF+/+497
—MEF2−/−10
—MEF3−/−5
—MEF+/+14
|
[0079] Chimeric oligonucleotide (1.5 μg) or modified single-stranded oligonucleotide (0.55 μg) was incubated with 1 μg of plasmid pKsm4021 and 20 μg of the indicated extracts. MEF represents mouse embryonic fibroblasts with either MSH2 (2−/−) or MSH3 (3−/−) deleted. MEF+/+ indicates wild-type mouse embryonic fibroblasts. The other reaction components were then added and processed through the bacterial readout system. The data represent the number of kanamycin resistant colonies per 106 ampicillin resistant colonies.
4TABLE III
|
|
Frameshift mutation repair is directed by
single-stranded oligonucleotides
OligonucleotidePlasmidExtracttetr colonies
|
Tet IX (3S125A; 0.5 μg)pTSΔ208 (1 μg)0
—pTSΔ208 (1 μg)20 μg0
Tet IX (0.5 μg)pTSΔ208 (1 μg)20 μg48
Tet IX (1.5 μg)pTSΔ208 (1 μg)20 μg130
Tet IX (2.0 μg)pTSΔ208 (1 μg)20 μg68
Tet I (chimera; 1.5 μg)pTSΔ208 (1 μg)20 μg48
|
[0080] Each reaction mixture contained the indicated amounts of plasmid and oligonucleotide. The extract used for these experiments came from HUH7 cells. The data represent the number of tetracycline resistant colonies per 106 ampicillin resistant colonies generated from the same reaction and is the average of 3 independent experiments. Tet I is a chimeric oligonucleotide and Tet IX is a modified single-stranded oligonucleotide that are designed to insert a T residue at position 208 of pTsΔ208. These oligonucleotides are equivalent to structures I and IX in FIG. 2.
5TABLE IV
|
|
Plant cell-free extracts support gene repair by
single-stranded oligonucleotides
OligonucleotidePlasmidExtractkanr colonies
|
II (chimera)pKSm402130 μgCanola337
IX (3S/25G)pKSm4021Canola763
X (6S/25G)pKSm4021Canola882
IIpKSm4021Musa203
IXpKSm4021Musa343
XpKSm4021Musa746
—pKSm4021Canola0
—pKSm4021Musa0
IXpKSm4021—Canola0
XpKSm4021—Musa0
|
[0081] Canola or Musa cell-free extracts were tested for gene repair activity on the kanamycin-sensitive gene as previously described in (18). Chimeric oligonucleotide II (1.5 μg) and modified single-stranded oligonucleotides IX and X (0.55 μg) were used to correct pKsm4021. Total number of kanr colonies are present per 107 ampicillin resistant colonies and represent an average of four independent experiments.
6TABLE V
|
|
Gene repair activity in cell-free extracts prepared
from yeast (Saccharomyces cerevisiae)
Cell-typePlasmidChimeric OligoSS Oligokanr/ampr × 106
|
Wild typepKanSm40211 μg0.36
Wild typepKanSm40211 μg0.81
ΔRAD52pKanSm40211 μg10.72
ΔRAD52pKanSm40211 μg17.41
ΔPMS1pKanSm40211 μg2.02
ΔPMS1pKanSm40211 μg3.23
|
In this experiment, the kanr gene in pKanS4021 is corrected by either a chimeric double-hairpin oligonucleotide or a single-stranded oligonucleotide containing three thioate linkages at each end (3S/25G).
Yeast Cell Targeting Assay Method for Base Alteration and Preferred Oligonucleotide Selection
[0082] In this example, single-stranded oligonucleotides with modified backbones and double-hairpin oligonucleotides with chimeric, RNA-DNA backbones are used to measure gene repair using two episomal targets with a fusion between a hygromycin resistance gene and eGFP as a target for gene repair. These plasmids are pAURHYG(rep)GFP, which contains a point mutation in the hygromycin resistance gene (FIG. 7), pAURHYG(ins)GFP, which contains a single-base insertion in the hygromycin resistance gene (FIG. 7) and pAURHYG(A)GFP which has a single base deletion. We also use the plasmid containing a wild-type copy of the hygromycin-eGFP fusion gene, designated pAURHYG(wt)GFP, as a control. These plasmids also contain an aureobasidinA resistance gene. In pAURHYG(rep)GFP, hygromycin resistance gene function and green fluorescence from the eGFP protein are restored when a G at position 137, at codon 46 of the hygromycin B coding sequence, is converted to a C thus removing a premature stop codon in the hygromycin resistance gene coding region. In pAURHYG(ins)GFP, hygromycin resistance gene function and green fluorescence from the eGFP protein are restored when an A inserted between nucleotide positions 136 and 137, at codon 46 of the hygromycin B coding sequence, is deleted and a C is substituted for the T at position 137, thus correcting a frameshift mutation and restoring the reading frame of the hygromycin-eGFP fusion gene.
[0083] We synthesize the set of three yeast expression constructs pAURHYG(rep)eGFP, pAURHYG(Δ)eGFP, pAURHYG(ins)eGFP, that contain a point mutation at nucleotide 137 of the hygromycin-B coding sequence as follows. (rep) indicates a T137→G replacement, (Δ) represents a deletion of the G137 and (ins) represents an A insertion between nucleotides 136 and 137. We construct this set of plasmids by excising the respective expression cassettes by restriction digest from pHyg(x)EGFP and ligation into pAUR123 (Panvera, Calif.). We digest 10 μg pAUR123 vector DNA, as well as, 10 μg of each pHyg(x)EGFP construct with Kpnl and Sall (NEB). We gel purify each of the DNA fragments and prepare them for enzymatic ligation. We ligate each mutated insert into pHygEGFP vector at 3:1 molar ration using T4 DNA ligase (Roche). We screen clones by restriction digest, confirm by Sanger dideoxy chain termination sequencing and purify using a Qiagen maxiprep kit.
[0084] We use this system to assay the ability of five oligonucleotides (shown in FIG. 8) to support correction under a variety of conditions. The oligonucleotides which direct correction of the mutation in pAURHYG(rep)GFP can also direct correction of the mutation in pAURHYG(ins)GFP. Three of the four oligonucleotides (HygE3T/25, HygE3T/74 and HygGG/Rev) share the same 25-base sequence surrounding the base targeted for alteration. HygGG/Rev is an RNA-DNA chimeric double hairpin oligonucleotide of the type described in the prior art. One of these oligonucleotides, HygE3T/74, is a 74-base oligonucleotide with the 25-base sequence centrally positioned. The fourth oligonucleotide, designated HygE3T/74α, is the reverse complement of HygE3T/74. The fifth oligonucleotide, designated Kan70T, is a non-specific, control oligonucleotide which is not complementary to the target sequence. Alternatively, an oligonucleotide of identical sequence but lacking a mismatch to the target or a completely thioate modified oligonucleotide or a completely 2-O-methylated modified oligonucleotide may be used as a control.
[0085] Oligonucleotide synthesis and cells. We synthesized and purified the chimeric, double-hairpin oligonucleotides and single-stranded oligonucleotides (including those with the indicated modifications) as described in Example 1. Plasmids used for assay were maintained stably in yeast (Saccharomyces cerevisiae) strain LSY678 MATα at low copy number under aureobasidin selection. Plasmids and oligonucleotides are introduced into yeast cells by electroporation as follows: to prepare electrocompetent yeast cells, we inoculate 10 ml of YPD media from a single colony and grow the cultures overnight with shaking at 300 rpm at 30° C. We then add 30 ml of fresh YPD media to the overnight cultures and continue shaking at 30° C. until the OD600 was between 0.5 and 1.0 (3-5 hours). We then wash the cells by centrifuging at 4° C. at 3000 rpm for 5 minutes and twice resuspending the cells in 25 ml ice-cold distilled water. We then centrifuge at 4° C. at 3000 rpm for 5 minutes and resuspend in 1 ml ice-cold 1 M sorbitol and then finally centrifuge the cells at 4° C. at 5000 rpm for 5 minutes and resuspend the cells in 120 μl 1M sorbitol. To transform electrocompetent cells with plasmids or oligonucleotides, we mix 40 μl of cells with 5 μg of nucleic acid, unless otherwise stated, and incubate on ice for 5 minutes. We then transfer the mixture to a 0.2 cm electroporation cuvette and electroporate with a BIO-RAD Gene Pulser apparatus at 1.5 kV, 25 μF, 200 Ω for one five-second pulse. We then immediately resuspend the cells in 1 ml YPD supplemented with 1M sorbitol and incubate the cultures at 30° C. with shaking at 300 rpm for 6 hours. We then spread 200 μl of this culture on selective plates containing 300 μg/ml hygromycin and spread 200 μl of a 105 dilution of this culture on selective plates containing 500 ng/ml aureobasidinA and/or and incubate at 30° C. for 3 days to allow individual yeast colonies to grow. We then count the colonies on the plates and calculate the gene conversion efficiency by determining the number of hygromycin resistance colonies per 105 aureobasidinA resistant colonies.
[0086] Frameshift mutations are repaired in yeast cells. We test the ability of the oligonucleotides shown in FIG. 8 to correct a frameshift mutation in vivo using LSY678 yeast cells containing the plasmid pAURHYG(ins)GFP. These experiments, presented in Table 6, indicate that these oligonucleotides can support gene correction in yeast cells. These data reinforce the results described in Example 1 indicating that oligonucleotides comprising phosphorothioate linkages facilitate gene correction much more efficiently than control duplex, chimeric RNA-DNA oligonucleotides. This gene correction activity is also specific as transformation of cells with the control oligonucleotide Kan70T produced no hygromycin resistant colonies above background and thus Kan70T did not support gene correction in this system. In addition, we observe that the 74-base oligonucleotide (HygE3T/74) corrects the mutation in pAURHYG(ins)GFP approximately five-fold more efficiently than the 25-base oligonucleotide (HygE3T/25). We also perform control experiments with LSY678 yeast cells containing the plasmid pAURHYG(wt)GFP. With this strain we observed that even without added oligonucleotides, there are too many hygromycin resistant colonies to count.
[0087] We also use additional oligonucleotides to assay the ability of individual oligonucleotides to correct multiple mutations in the pAURHYG(x)eGFP plasmid. These include, for example, one that alters two basepairs that are 3 nucleotides apart is a 74-mer with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGGTACGTCCTGCGGGTAAATAGCTGCGCCGATG GTTTCTAC-3′; a 74-mer that alters two basepairs that are 15 nucleotides apart with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAACAGCTGCGCCGATG GTTTCTAC-3′; and a 74-mer that alters two basepairs that are 27 nucleotides apart with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAATAGCTGCGCCGACG GTTTCTAC. The nucleotides in these oligonucleotides that direct alteration of the target sequence are underlined and in boldface. These oligonucleotides are modified in the same ways as the other oligonucleotides of the invention.
[0088] Oligonucleotides targeting the sense strand direct gene coffection more efficiently. We compare the ability of single-stranded oligonucleotides to target each of the two strands of the target sequence of both pAURHYG(ins)GFP and pAURHYG(rep)GFP. These experiments, presented in Tables 7 and 8, indicate that an oligonucleotide, HygE3T/74α, with sequence complementary to the sense strand (i.e. the strand of the target sequence that is identical to the mRNA) of the target sequence facilitates gene correction approximately ten-fold more efficiently than an oligonucleotide, HygE3T/74, with sequence complementary to the non-transcribed strand which serves as the template for the synthesis of RNA. As indicated in Table 7, this effect was observed over a range of oligonucleotide concentrations from 0-3.6 μg, although we did observe some variability in the difference between the two oligonucleotides (indicated in Table 7 as a fold difference between HygE3T/74α and HygE3T/74). Furthermore, as shown in Table 8, we observe increased efficiency of correction by HygE3T/74α relative to HygE3T/74 regardless of whether the oligonucleotides were used to correct the base substitution mutation in pAURHYG(rep)GFP or the insertion mutation in pAURHYG(ins)GFP. The data presented in Table 8 further indicate that the single-stranded oligonucleotides correct a base substitution mutation more efficiently than an insertion mutation. However, this last effect was much less pronounced and the oligonucleotides of the invention are clearly able efficiently to correct both types of mutations in yeast cells. In addition, the role of transcription is investigated using plasmids with inducible promoters such as that described in FIG. 10.
[0089] Optimization of oligonucleotide concentration. To determine the optimal concentration of oligonucleotide for the purpose of gene alteration, we test the ability of increasing concentrations of Hyg3T/74α to correct the mutation in pAURHYG(rep)GFP contained in yeast LSY678. We chose this assay system because our previous experiments indicated that it supports the highest level of correction. However, this same approach could be used to determine the optimal concentration of any given oligonucleotide. We test the ability of Hyg3T/74α to correct the mutation in pAURHYG(rep)GFP contained in yeast LSY678 over a range of oligonucleotide concentrations from 0-10.0 μg. As shown in Table 9, we observe that the correction efficiency initially increases with increasing oligonucleotide concentration, but then declines at the highest concentration tested.
[0090] Tables are attached hereto.
7TABLE 6
|
|
Correction of an insertion mutation in pAURHYG(ins)GFP
by HygGG/Rev, HygE3T/25 and HygE3T/74
OligonucleotideColonies onColonies onCorrection
TestedHygromycinAureobasidin (/105)Efficiency
|
HygGG/Rev31570.02
HygE3T/25641470.44
HygE3T/742801741.61
Kan70T0——
|
[0091]
8
TABLE 7
|
|
|
An oligonucleotide targeting the sense strand of the target
|
sequence corrects more efficiently.
|
Colonies per hygromycin plate
|
Amount of Oligonuleotide (μg)
HygE3T/74
HygE3T/74α
|
|
0
0
0
|
0.6
24
128 (8.4x)*
|
1.2
69
140 (7.5x)*
|
2.4
62
167 (3.8x)*
|
3.6
29
367 (15x)*
|
|
*The numbers in parentheses represent the fold increase in efficiency for targeting the non-transcribed strand as compared to the other strand of a DNA duplex that encodes a protein.
|
[0092]
9
TABLE 8
|
|
|
Correction of a base substitution mutation is more
|
efficient than correction of a frame shift mutation.
|
Oligonucleotide
Plasmid tested (contained in LSY678)
|
Tested (5 μg)
pAURHYG(ins)GFP
pAURHYG(rep)GFP
|
|
HygE3T/74
72
277
|
HygE3T/74α
1464
2248
|
Kan70T
0
0
|
|
[0093]
10
TABLE 9
|
|
|
Optimization of oligonucleotide concentration in
|
electroporated yeast cells.
|
Amount
Colonies on
Colonies on
Correction
|
(μg)
hygromycin
aureobasidin (/105)
efficiency
|
|
0
0
67
0
|
1.0
5
64
0.08
|
2.5
47
30
1.57
|
5.0
199
33
6.08
|
7.5
383
39
9.79
|
10.0
191
33
5.79
|
|
Cultured Cell Manipulation
[0094] Mononuclear cells are isolated from human umbilical cord blood of normal donors using Ficoll Hypaque (Pharmacia Biotech, Uppsala, Sweden) density centrifugation. CD 34+cells are immunomagnetically purified from mononuclear cells using either the progenitor or Multisort Kits (Miltenyi Biotec, Auburn, Calif.). Lin−CD38− cells are purified from the mononuclear cells using negative selection with StemSep system according to the manufacturer's protocol (Stem Cell Technologies, Vancouver, Calif.). Cells used for microinjection are either freshly isolated or cryopreserved and cultured in Stem Medium (S Medium) for 2 to 5 days prior to microinjection. S Medium contains Iscoves' Modified Dulbecco's Medium without phenol red (IMDM) with 100 μg/ml glutamine/penicillin/streptomycin, 50 mg/ml bovine serum albumin, 50 μg/ml bovine pancreatic insulin, 1 mg/ml human transferrin, and IMDM; Stem Cell Technologies), 40 μg/ml low-density lipoprotein (LDL; Sigma, St. Louis, Mo.), 50 mM HEPEs buffer and 50 μM 2-mercaptoethanol, 20 ng/ml each of thrombopoietin, flt-3 ligand, stem cell factor and human IL-6 (Pepro Tech Inc., Rocky Hill, N.J.). After microinjection, cells are detached and transferred in bulk into wells of 48 well plates for culturing.
[0095] 35 mm dishes are coated overnight at 40 C with 50 μg/ml Fibronectin (FN) fragment CH-296 (Retronectin; TaKaRa Biomedicals, Panvera, Madison, Wis.) in phosphate buffered saline and washed with IMDM containing glutamine/penicillin/streptomycin. 300 to 2000 cells are added to cloning rings and attached to the plates for 45 minutes at 37° C. prior to microinjection. After incubation, cloning rings are removed and 2 ml of S Medium are added to each dish for microinjection. Pulled injection needles with a range of 0.22 μ to 0.3 μ outer tip diameter are used. Cells are visualized with a microscope equipped with a temperature controlled stage set at 37° C. and injected using an electronically interfaced Eppendorf Micromanipulator and Transjector. Successfully injected cells are intact, alive and remain attached to the plate post injection. Molecules that are flourescently labeled allow determination of the amount of oligonucleotide delivered to the cells.
[0096] For in vitro erythropoiesis from Lin−CD38− cells, the procedure of Malik, 1998 can be used. Cells are cultured in ME Medium for 4 days and then cultured in E Medium for 3 weeks. Erythropoiesis is evident by glycophorin A expression as well as the presence of red color representing the presence of hemoglobin in the cultured cells. The injected cells are able to retain their proliferative capacity and the ability to generate myeloid and erythoid progeny. CD34+cells can convert a normal A (βA) to sickle T (βS) mutation in the β-globin gene or can be altered using any of the oligonucleotides of the invention herein for correction or alteration of a normal gene to a mutant gene. Alternatively, stem cells can be isolated from blood of humans having genetic disease mutations and the oligonucleotides of the invention can be used to correct a defect or to modify genomes within those cells.
[0097] Alternatively, non-stem cell populations of cultured cells can be manipulated using any method known to those of skill in the art including, for example, the use of polycatons, cationic lipids, liposomes, polyethylenimine (PEI), electroporation, biolistics, calcium phophate precipitation, or any other method known in the art.
[0098] Notes on the Tables Presented Below:
[0099] Each of the following tables presents, for the specified human gene, a plurality of mutations that are known to confer a clinically-relevant phenotype and, for each mutation, the oligonucleotides that can be used to correct the respective mutation site-specifically in the human genome according to the present invention.
[0100] The left-most column identifies each mutation and the clinical phenotype that the mutation confers.
[0101] For most entries, the mutation is identified at both the nucleic acid and protein level. At the amino acid level, mutations are presented according to the following standard nomenclature. The centered number identifies the position of the mutated codon in the protein sequence; to the left of the number is the wild type residue and to the right of the number is the mutant codon. Codon numbering is according to the Human Gene Mutation Database, Cardiff, Wales, UK (http://archive.uwcm.ac.uk/search/mg/allgenes). Terminator codons are shown as “TERM”. At the nucleic acid level, the entire triplet of the wild type and mutated codons is shown.
[0102] The middle column presents, for each mutation, four oligonucleotides capable of repairing the mutation site-specifically in the human genome or in cloned human DNA including human DNA in artificial chromosomes, episomes, plasmids, or other types of vectors. The oligonucleotides of the invention, however, may include any of the oligonucleotides sharing portions of the sequence of the 121 base sequence. Thus, oligonucleotides of the invention for each of the depicted targets may be 18, 19, 20 up to about 121 nucleotides in length. Sequence may be added non-symmetrically.
[0103] All oligonucleotides are presented, per convention, in the 5′ to 3′ orientation. The nucleotide that effects the change in the genome is underlined and presented in bold.
[0104] The first of the four oligonucleotides for each mutation is a 121 nt oligonucleotide centered about the repair nucleotide. The second oligonucleotide, its reverse complement, targets the opposite strand of the DNA duplex for repair. The third oligonucleotide is the minimal 17 nt domain of the first oligonucleotide, also centered about the repair nucleotide. The fourth oligonucleotide is the reverse complement of the third, and thus represents the minimal 17 nt domain of the second.
[0105] The third column of each table presents the SEQ ID NO: of the respective repair oligonucleotide.
Adenosine Deaminase (ADA)
[0106] Adenosine deaminase (ADA, EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine or 2′-deoxyinosine respectively. ADA deficiency has been identified as the metabolic basis for 20-30% of cases with recessively inherited severe combined immunodeficiency (SCID). Affected infants are subject to recurrent chronic viral, fungal, protozoal, and bacterial infections and frequently present with persistent diarrhea, failure to thrive and candidiasis. In patents homozygous for ADA deficiency, 2′-deoxyadenosine accumulating during the rapid turnover of cells rich in DNA is converted back to dATP, either by adenosine kinase or deoxycytidine kinase. Many hypotheses have been advanced to explain the specific toxicity to the immune system in ADA deficiency. The apparently selective accumulation of dATP in thymocytes and peripheral blood B cells, with resultant inhibition of ribonucleotide reductase and DNA synthesis is probably the principal mechanism.
[0107] The structural gene for ADA is encoded as a single 32 kb locus containing 12 exons. Studies of the molecular defect in ADA-deficient patents have shown that mRNA is usually detectable in normal or supranormal amounts. Specific base substitution mutations have been detected in the majority of cases with the complete deficiency. A C-to-T base substitution mutation in exon 11 accounts for a high proportion of these, whilst a few patents are homozygous for large deletions encompassing exon 1. A common point mutation resulting in a heat-labile ADA has been characterised in some patients with partial ADA deficiency, a disorder with an apparently increased prevalence in the Caribbean.
[0108] As yet no totally effective therapy for ADA deficiency has been reported, except in those few cases where bone marrow from an HLA/MLR compatible sibling donor was available.
[0109] Two therapeutic approaches have provided long-term benefit in specific instances. First, reconstitution using T cell depleted mismatched sibling marrow has been encouraging, particularly in early presenters completely deficient in ADA. Secondly, therapy with polyethylene glycol-modified adenosine deaminase (PEG-ADA) for more than 5 years has produced a sustained increase in lymphocyte numbers and mitogen responses together with evidence of in vivo B cell function. Success has generally been achieved in late presenters with residual ADA activity in mononuclear cells.
[0110] ADA deficiency has been chosen as the candidate disease for gene replacement therapy and the first human experiment commenced in 1990. The clinical consequences of overexpression of ADA activity—one of the potential hazards of gene implant—are known and take the form of an hereditary haemolytic anaemia associated with a tissue-specific increase in ADA activity. The genetic basis for the latter autosomal dominant disorder seemingly relates to markedly increased levels of structurally normal ADA mRNA.
11TABLE 10
|
|
ADA Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Adenosine deaminaseAGAGACCCACCGAGCGGCGGCGGAGGGAGCAGCGCCGGGG1
deficiencyCGCACGAGGGCACCATGGCCCAGACGCCCGCCTTCGACAAG
GLN3TERMCCCAAAGTGAGCGCGCGCGGGGGCTCCGGGGACGGGGGTC
CAG to TAGGACCCCCGTCCCCGGAGCCCCCGCGCGCGCTCACTTTGGG2
CTTGTCGAAGGCGGGCGTCTGGGCCATGGTGCCCTCGTGCG
CCCCGGCGCTGCTCCCTCCGCCGCCGCTCGGTGGGTCTCT
CCATGGCCCAGACGCCC3
GGGCGTCTGGGCCATGG4
Adenosine deaminaseTATTTGTTCTCTCTCTCCCTTTCTCTCTCTCTTCCCCCTGCCC5
deficiencyCCTTGCAGGTAGAACTGCATGTCCACCTAGACGGATCCATCA
HIS15ASPAGCCTGAAACCATCTTATACTATGGCAGGTAAGTCC
CAT to GATGGACTTACCTGCCATAGTATAAGATGGTTTCAGGCTTGATGGA6
TCCGTCTAGGTGGACATGCAGTTCTACCTGCAAGGGGGCAG
GGGGAAGAGAGAGAGAAAGGGAGAGAGAGAACAAATA
TAGAACTGCATGTCCAC7
GTGGACATGCAGTTCTA8
Adenosine deaminaseTCCCTTTCTCTCTCTCTTCCCCCTGCCCCCTTGCAGGTAGAA9
deficiencyCTGCATGTCCACCTAGACGGATCCATCAAGCCTGAAACCATC
GLY20ARGTTATACTATGGCAGGTAAGTCCATACAGAAGAGCCCT
GGA to AGAAGGGCTCTTCTGTATGGACTTACCTGCCATAGTATAAGATGGT10
TTCAGGCTTGATGGATCCGTCTAGGTGGACATGCAGTTCTAC
CTGCAAGGGGGCAGGGGGAAGAGAGAGAGAAAGGGA
ACCTAGACGGATCCATC11
GATGGATCCGTCTAGGT12
Adenosine deaminaseCCTGGAGCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACC13
deficiencyCCTTTCTTCCCTTCCCAGGGGCTGCCGGGAGGCTATCAAAAG
GLY74CYSGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGG
GGC to TGCCCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCTTTT14
GATAGCCTCCCGGCAGCCCCTGGGAAGGGAAGAAAGGGGTT
GGGAACAACCTTCCCCAAGTCCCTTGGGAGCTCCAGG
CTATCGCGGGCTGCCGG15
CCGGCAGCCCGCGATAG16
Adenosine DeaminaseGCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACCCCTTTCT17
DeficiencyTCCCTTCCCAGGGGCTGCCGGGAGGCTATCAAAAGGATCGC
ARG76TRPCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGG
CGG to TGGCCACGCCCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGAT18
CCTTTTGATAGCCTCCCGGCAGCCCCTGGGAAGGGAAGAAA
GGGGTTGGGAACAACCTTCCCCAAGTCCCTTGGGAGC
GGGGCTGCCGGGAGGCT19
AGCCTCCCGGCAGCCCC20
Adenosine DeaminaseTTGGGGAAGGTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGG21
DeficiencyGCTGCCGGGAGGCTATCAAAAGGATCGCCTATGAGTTTGTAG
LYS80ARGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGT
AAA to AGAACCTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTACAA22
ACTCATAGGCGATCCTTTTGATAGCCTCCCGGCAGCCCCTGG
GAAGGGAAGAAAGGGGTTGGGAACAACCTTCCCCAA
GGCTATCAAAAGGATCG23
CGATCCTTTTGATAGCC24
Adenosine deaminaseGTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGGGCTGCCGGG25
deficiencyAGGCTATCAAAAGGATCGCCTATGAGTTTGTAGAGATGAAGG
ALA83ASPCCAAAGAGGGCGTGGTGTATGTGGAGGTGCGGTACAG
GCC to GACCTGTACCGCACCTCCACATACACCACGCCCTCTTTGGCCTTC26
ATCTCTACAAACTCATAGGCGATCCTTTTGATAGCCTCCCGGC
AGCCCCTGGGAAGGGAAGAAAGGGGTTGGGAACAAC
AAGGATCGCCTATGAGT27
ACTCATAGGCGATCCTT28
Adenosinoe deaminaseAGGCTATCAAAAGGATCGCCTATGAGTTTGTAGAGATGAAGG29
deficiencyCCAAAGAGGGCGTGGTGTATGTGGAGGTGCGGTACAGTCCG
TYR97CYSCACCTGCTGGCCAACTCCAAAGTGGAGCCAATCCCCTG
TAT to TGTCAGGGGATTGGCTCCACTTTGGAGTTGGCCAGCAGGTGCGG30
ACTGTACCGCACCTCCACATACACCACGCCCTCTTTGGCCTT
CATCTCTACAAACTCATAGGCGATCCTTTTGATAGCCT
CGTGGTGTATGTGGAGG31
CCTCCACATACACCACG32
Adenosine deaminseGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG33
deficiencyTGGTGTATGTGGAGGTGCGGTACAGTCCGCACCTGCTGGCC
ARG101GLNAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA
CGG to CAGTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGC34
AGCAGGTGCGGACTGTACCGCACCTCCACATACACCACGCC
CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC
GGAGGTGCGGTACAGTC35
GACTGTACCGCACCTCC36
Adenosine deaminaseGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG37
deficiencyTGGTGTATGTGGAGGTGCGGTACAGTCCGCACCTGCTGGCC
ARG101LEUAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA
CGG to CTGTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCC38
AGCAGGTGCGGACTGTACCGCACCTCCACATACACCACGCC
CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC
GGAGGTGCGGTACAGTC39
GACTGTACCGCACCTCC40
Adenosine deaminaseAGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGC41
deficiencyGTGGTGTATGTGGAGGTGCGGTACAGTCCGCACCTGCTGGC
ARG101TRPCAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTG
CGG to TGGCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCCA42
GCAGGTGCGGACTGTACCGCACCTCCACATACACCACGCCC
TCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCT
TGGAGGTGCGGTACAGT43
ACTGTACCGCACCTCCA44
Adenosine deaminaseATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATG45
deficiencyTGGAGGTGCGGTACAGTCCGCACCTGCTGGCCAACTCCAAA
PRO104LEUGTGGAGCCAATCCCCTGGAACCAGGCTGAGTGAGTGAT
CCG to CTGATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTG46
GAGTTGGCCAGCAGGTGCGGACTGTACCGCACCTCCACATA
CACCACGCCCTCTTTGGCCTTCATCTCTACAAACTCAT
GTACAGTCCGCACCTGC47
GCAGGTGCGGACTGTAC48
Adenosine deaminaseTTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAG49
deficiencyGTGCGGTACAGTCCGCACCTGCTGGCCAACTCCAAAGTGGA
LEU106VALGCCAATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCC
CTG to GTGGGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCA50
CTTTGGAGTTGGCCAGCAGGTGCGGACTGTACCGCACCTCC
ACATACACCACGCCCTCTTTGGCCTTCATCTCTACAAA
GTCCGCACCTGCTGGCC51
GGCCAGCAGGTGCGGAC52
Adenosine deaminaseTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGTG53
deficiencyCGGTACAGTCCGCACCTGCTGGCCAACTCCAAAGTGGAGCC
LEU107PROAATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCCTGGA
CTG to CCGTCCAGGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGC54
TCCACTTTGGAGTTGGCCAGCAGGTGCGGACTGTACCGCAC
CTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTA
GCACCTGCTGGCCAACT55
AGTTGGCCAGCAGGTGC56
Adenosine deaminaseGCCTTCCTTTTGCCTCAGGCCCATCCCTACTCCTCTCCTCAC57
deficiencyACAGAGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTG
PRO126GLNGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGT
CCA to CAAACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCAC58
TAGGGCCACCACCTCGTCTGGGGTGAGGTCCCCTCTGTGTG
AGGAGAGGAGTAGGGATGGGCCTGAGGCAAAAGGAAGGC
CCTCACCCCAGACGAGG59
CCTCGTCTGGGGTGAGG60
Adenosine deaminaseTTTGCCTCAGGCCCATCCCTACTCCTCTCCTCACACAGAGGG61
deficiencyGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCAGGG
VAL129METCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC
GTG to ATG GGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCC62
TGGCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCC
TCTGTGTGAGGAGAGGAGTAGGGATGGGCCTGAGGCAAA
CAGACGAGGTGGTGGCC63
GGCCACCACCTCGTCTG64
Adenosine deaminaseACAGAGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTG65
deficiencyGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCA
GLY140GLUAGGCCCGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAG
GGG to GAG CTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGGGCCTT66
GACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCA
CTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCCTCTGT
GCAGGAGGGGGAGCGAG67
CTCGCTCCCCCTCCTGC68
Adenosine deaminaseGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCAG69
deficiencyGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC
ARG142GLNGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGTA
CGA to CAATACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCG70
GGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCT
GGCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCC
GGGGGAGCGAGACTTCG71
CGAAGTCTCGCTCCCCC72
Adenosine deaminaseGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCA73
deficiencyGGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCC
ARG142TERMCGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGT
CGA to TGAACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGG74
GCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCTG
GCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCC
AGGGGGAGCGAGACTTC75
GAAGTCTCGCTCCCCCT76
Adenosine deaminaseTGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCG77
deficiencyAGACTTCGGGGTCAAGGCCCGGTCCATCCTGTGCTGCATGC
ARG149GLNGCCACCAGCCCAGTGAGTAGGATCACCGCCCTGCCCAGGG
CGG to CAGCCCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCG78
CATGCAGCACAGGATGGACCGGGCCTTGACCCCGAAGTCTC
GCTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCA
CAAGGCCCGGTCCATCC79
GGATGGACCGGGCCTTG80
Adenosine deaminaseGTGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGC81
deficiencyGAGACTTCGGGGTCAAGGCCCGGTCCATCCTGTGCTGCATG
ARG149TRPCGCCACCAGCCCAGTGAGTAGGATACCGCCCTGCCCAGG
CGG to TGGCCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCGC82
ATGCAGCACAGGATGGACCGGGCCTTGACCCCGAAGTCTCG
CTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCAC
TCAAGGCCCGGTCCATC83
GATGGACCGGGCCTTGA84
Adenosine deaminaseCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCG85
deficiencyGGGTCAAGGCCCGGTCCATCCTGTGCTGCATGCGCCACCAG
LEU152METCCCAGTGAGTAGGATCACCGCCCTGCCCAGGGCCGCCCGT
CTG to ATGACGGGCGGCCCTGGGCAGGGCGGTGATCCTACTCACTGGG86
CTGGTGGCGCATGCAGCACAGGATGGACCGGGCCTTGACCC
CGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCACTAG
GGTCCATCCTGTGCTGC87
GCAGCACAGGATGGACC88
Adenosine deaminaseGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC89
deficiencyGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGTAG
ARG156CYSGATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCC
CGC to TGCGGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGATC90
CTACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACC
GGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCC
GCTGCATGCGCCACCAG91
CTGGTGGCGCATGCAGC92
Adenosine deaminaseGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCCG93
deficiencyGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGTAGG
ARG156HISATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCCC
CGC to CACGGGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGAT94
CCTACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGAC
CGGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGC
CTGCATGCGCCACCAGC95
GCTGGTGGCGCATGCAG96
Adenosine deaminaseCTGCCCACAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAA97
deficiencyGAAGTACCAGCAGCAGACCGTGGTAGCCATTGACCTGGCTG
VAL177METGAGATGAGACCATCCCAGGAAGCAGCCTCTTGCCTGGAC
GTG to ATGGTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCATCTCCAG98
CCAGGTCAATGGCTACCACGGTCTGCTGCTGGTACTTCTTAC
ACAGCTCCACCACCTTGGGGGACCAGTCTGTGGGCAG
AGCAGACCGTGGTAGCC99
GGCTACCACGGTCTGCT100
Adenosine deaminaseCAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAAGAAGTAC101
deficiencyCAGCAGCAGACCGTGGTAGCCATTGACCTGGCTGGAGATGA
ALA179ASPGACCATCCCAGGAAGCAGCCTCTTGCCTGGACATGTCCA
GCC to GACTGGACATGTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCA102
TCTCCAGCCAGGTCAATGGCTACCACGGTCTGCTGCTGGTAC
TTCTTACACAGCTCCACCACCTTGGGGGACCAGTCTG
CGTGGTAGCCATTGACC103
GGTCAATGGCTACCACG104
Adenosine deaminaseCCATTGACCTGGCTGGAGATGAGACCATCCCAGGAAGCAGC105
deficiencyCTCTTGCCTGGACATGTCCAGGCCTACCAGGTGGGTCCTGT
GLN199PROGAGAAGGAATGGAGAGGCTGGCCCTGGGTGAGCTTGTCT
CAG to CCGAGACAAGCTCACCCAGGGCCAGCCTCTCCATTCCTTCTCACA106
GGACCCACCTGGTAGGCCTGGACATGTCCAGGCAAGAGGCT
GCTTCCTGGGATGGTCTCATCTCCAGCCAGGTCAATGG
ACATGTCCAGGCCTACC107
GGTAGGCCTGGACATGT108
Adenosine deaminaseGCTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGCC109
deficiencyTGTGAAGAGCGGCATTCACCGTACTGTCCACGCCGGGGAGG
ARG211CYSTGGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGG
CGT to TGTCCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACCT110
CCCCGGCGTGGACAGTACGGTGAATGCCGCTCTTCACAGCC
TCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAGC
GCATTCACCGTACTGTC111
GACAGTACGGTGAATGC112
Adenosine deaminaseCTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGCT113
deficiencyGTGAAGAGCGGCATTCACCGTACTGTCCACGCCGGGGAGGT
ARG211HISGGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGGC
CGT to CATGCCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACC114
TCCCCGGCGTGGACAGTACGGTGAATGCCGCTCTTCACAGC
CTCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAG
CATTCACCGTACTGTCC115
GGACAGTACGGTGAATG116
Adenosine deaminaseATGACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGG117
deficiencyCATTCACCGTACTGTCCACGCCGGGGAGGTGGGCTCGGCCG
ALA215THRAAGTAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGG
GCC to ACCCCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTACTTCGG118
CCGAGCCCACCTCCCCGGCGTGGACAGTACGGTGAATGCCG
CTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGTCAT
CTGTCCACGCCGGGGAG119
CTCCCCGGCGTGGACAG120
Adenosine deaminaseACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCAT121
deficiencyTCACCGTACTGTCCACGCCGGGGAGGTGGGCTCGGCCGAAG
GLY216ARGTAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCC
GGG to AGGGGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTACTT122
CGGCCGAGCCCACCTCCCCGGCGTGGACAGTACGGTGAATG
CCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGT
TCCACGCCGGGGAGGTG123
CACCTCCCCGGCGTGGA124
Adenosine deaminaseTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCATTCA125
deficiencyCCGTACTGTCCACGCCGGGGAGGTGGGCTCGGCCGAAGTAG
GLU217LYSTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCCCTC
GAG to AAGGAGGGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTA126
CTTCGGCCGAGCCCACCTCCCCGGCGTGGACAGTACGGTGA
ATGCCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCA
ACGCCGGGGAGGTGGGC127
GCCCACCTCCCCGGCGT128
Adenosine deaminaseCTGCCTCCTCCCATACTTGGCTCTATTCTGCTTCTCTACAGGC129
deficiencyTGTGGACATACTCAAGACAGAGCGGCTGGGACACGGCTACC
THR233ILEACACCCTGGAAGACCAGGCCCTTTATAACAGGCTGCG
ACA to ATACGCAGCCTGTTATAAAGGGCCTGGTCTTCCAGGGTGTGGTAG130
CCGTGTCCCAGCCGCTCTGTCTTGAGTATGTCCACAGCCTGT
AGAGAAGCAGAATAGAGCCAAGTATGGGAGGAGGCAG
ACTCAAGACAGAGCGGC131
GCCGCTCTGTCTTGAGT132
Adenosine deaminaseCAGAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAG133
deficiencyGCCCTTTATAACAGGCTGCGGCAGGAAAACATGCACTTCGAG
ARG253PROGTAAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGC
CGG to CCGGCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACCTC134
GAAGTGCATGTTTTCCTGCCGCAGCCTGTTATAAAGGGCCTG
GTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTCTG
CAGGCTGCGGCAGGAAA135
TTTCCTGCCGCAGCCTG136
Adenosine deaminaseGAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAGGC137
deficiencyCCTTTATAACAGGCTGCGGCAGGAAAACATGCACTTCGAGGT
GLN254TERMAAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGCTG
CAG to TAGCAGCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACC138
TCGAAGTGCATGTTTTCCTGCCGCAGCCTGTTATAAAGGGCC
TGGTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTC
GGCTGCGGCAGGAAAAC139
GTTTTCCTGCCGCAGCC140
Adenosine deaminaseCCACACACCTGCTCTTCCAGATCTGCCCCTGGTCCAGCTACC141
deficiencyTCACTGGTGCCTGGAAGCCGGACACGGAGCATGCAGTCATT
PRO274LEUCGGTGAGCTCTGTTCCCCTGGGCCTGTTCAATTTTGTT
CCG to CTGAACAAAATTGAACAGGCCCAGGGGAACAGAGCTCACCGAATG142
ACTGCATGCTCCGTGTCCGGCTTCCAGGCACCAGTGAGGTA
GCTGGACCAGGGGCAGATCTGGAAGAGCAGGTGTGTGG
CTGGAAGCCGGACACGG143
CCGTGTCCGGCTTCCAG144
Adenosine deaminaseGGAGGCTGATTCTCTCCTCCTCCCTCTTCTGCAGGCTCAAAA145
deficiencyATGACCAGGCTAACTACTCGCTCAACACAGATGACCCGCTCA
SER291LEUTCTTCAAGTCCACCCTGGACACTGATTACCAGATGAC
TCG to TTGGTCATCTGGTAATCAGTGTCCAGGGTGGACTTGAAGATGAGC146
GGGTCATCTGTGTTGAGCGAGTAGTTAGCCTGGTCATTTTTGA
GCCTGCAGAAGAGGGAGGAGGAGAGAATCAGCCTCC
TAACTACTCGCTCAACA147
TGTTGAGCGAGTAGTTA148
Adenosine deaminaseCCTCCCTCTTCTGCAGGCTCAAAAATGACCAGGCTAACTACT149
deficiencyCGCTCAACACAGATGACCCGCTCATCTTCAAGTCCACCCTGG
PRO297GLNACACTGATTACCAGATGACCAAACGGGACATGGGCTT
CCG to CAGAAGCCCATGTCCCGTTTGGTCATCTGGTAATCAGTGTCCAGG150
GTGGACTTGAAGATGAGCGGGTCATCTGTGTTGAGCGAGTAG
TTAGCCTGGTCATTTTTGAGCCTGCAGAAGAGGGAGG
AGATGACCCGCTCATCT151
AGATGAGCGGGTCATCT152
Adenosine deaminaseAAAATGACCAGGCTAACTACTCGCTCAACACAGATGACCCGC153
deficiencyTCATCTTCAAGTCCACCCTGGACACTGATTACCAGATGACCAA
LEU304ARGACGGGACATGGGCTTTACTGAAGAGGAGTTTAAAAG
CTG to CGGCTTTTAAACTCCTCTTCAGTAAAGCCCATGTCCCGTTTGGTCA154
TCTGGTAATCAGTGTCCAGGGTGGACTTGAAGATGAGCGGGT
CATCTGTGTTGAGCGAGTAGTTAGCCTGGTCATTTT
GTCCACCCTGGACACTG155
CAGTGTCCAGGGTGGAC156
Adenosine deaminaseGCCTTCTTTGTTCTCTGGTTCCATGTTGTCTGCCATTCTGGCC157
deficiencyTTTCCAGAACATCAATGCGGCCAAATCTAGTTTCCTCCCAGAA
ALA329VALGATGAAAAGAGGGAGCTTCTCGACCTGCTCTATAA
C-to-T at base 1081TTATAGAGCAGGTCGAGAAGCTCCCTCTTTTCATCTTCTGGGA158
GGAAACTAGATTTGGCCGCATTGATGTTCTGGAAAGGCCAGA
ATGGCAGACAACATGGAACCAGAGAACAAAGAAGGC
CATCAATGCGGCCAAAT159
ATTTGGCCGCATTGATG160
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P53 Mutations
[0111] The p53 gene codes for a protein that acts as a transcription factor and serves as a key regulator of the cell cycle. Mutation in this gene is probably the most significant genetic change characterizing the transformation of cells from normalcy to malignancy.
[0112] Inactivation of p53 by mutation disrupts the cell cycle which, in turn, sets the stage for tumor formation. Mutations in the p53 gene are among the most commonly diagnosed genetic disorders, occuring in as many as 50% of cancer patients. For some types of cancer, most notably of the breast, lung and colon, p53 mutations are the predominant genetic alternations found thus far. These mutations are associated with genomic instability and thus an increased susceptibility to cancer. Some p53 lesions result in malignancies that are resistant to the most widely used therapeutic regimens and therefore demand more aggressive treatment.
[0113] That p53 is associated with different malignant tumors is illustrated in the Li-Fraumeni autosomal dominant hereditary disorder characterized by familial multiple tumors due to mutation in the p53 gene. Affected individuals can develop one or more tumors, including: brain (12%); soft-tissue sarcoma (12%); breast cancer (25%); adrenal tumors (1%); bone cancer (osteosarcoma) (6%); cancer of the lung, prostate, pancreas, and colon as well as lymphoma and melanoma can also occur.
[0114] Certain of the most frequently mutated codons are codons 175, 248 and 273, however a variety of oligonucleotides are described below in the atttached table.
12TABLE 11
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p53 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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In 2 families withGACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCT161
Li-FraumeniGCATGGGCGGCATGAACCGGAGGCCCATCCTCACCATCATC
syndrome, there was aACACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACC
C-to-T mutation at theGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGA162
first nucleotide ofTGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGGAA
codon 248 whichCTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGTC
changed arginine toGCATGAACCGGAGGCCC163
tryptophan.GGGCCTCCGGTTCATGC164
In a family with theTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCAT165
Li-FraumeniCCTCACCATCATCACACTGGAAGACTCCAGGTCAGGAGCCAC
syndrome, a G-to-ATTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCCTC
mutation at the firstGAGGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGT166
nucleotide of codonGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGAT
258 resulting in theGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACT
substitution of lysineTCACACTGGAAGACTCC167
for glutamic acidGGAGTCTTCCAGTGTGA168
In a family with theGTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTA169
Li-FraumeniACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTC
syndrome, a G-to-TACCATCATCACACTGGAAGACTCCAGGTCAGGAGCCA
mutation atTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGA170
the first nucleotide ofTGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACACA
codon 245 resulting inTGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAAC
the substitution ofGCATGGGCGGCATGAAC171
cysteine for glycine.GTTCATGCCGCCCATGC172
A gly245-to-ser,
GGC-to-AGC,
mutation was found in
a patient in whom
osteosarcoma was
diagnosed at the age
of 18 years.
In a family with theTCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCA173
Li-FraumeniTGAACCGGAGGCCCATCCTCACCATCATCACACTGGAAGACT
syndrome, a germlineCCAGGTCAGGAGCCACTTGCCACCCTGCACACTGGCC
mutation at codon 252:GGCCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTC174
a T-to-C change at theTTCCAGTGTGATGATGGTGAGGATGGGCCTCCGGTTCATGCC
second positionGCCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGA
resulted in substitutionGCCCATCCTCACCATCA175
of proline for leucine.TGATGGTGAGGATGGGC176
Researchers analyzedTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATG177
for mutations in p53GGCGGCATGAACCGGAGGCCCATCCTCACCATCATCACACT
hepatocellularGGAAGACTCCAGGTCAGGAGCCACTTGCCACCCTGCA
carcinomas fromTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTG178
patients in Qidong, anTGATGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATG
area of high incidenceCAGGAACTGTTACACATGTAGTTGTAGTGGATGGTGGTA
in China, in which bothAACCGGAGGCCCATCCT179
hepatitis B virus andAGGATGGGCCTCCGGTT180
aflatoxin B1 are risk
factors. Eight of 16
tumors had a point
mutation at the third
base position of codon
249. The G-to-T
mutation at codon 249
led to a change from
arginine to serine
(AGG to AGT).
In cases ofCTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTCCACA181
hepatocellularCCCCCGCCCGGCACCCGCGTCCGCGCCATGGCCATCTACAA
carcinoma in southernGCAGTCACAGCACATGACGGAGGTTGTGAGGCGCTGCC
Africa, a G-to-TGGCAGCGCCTCACAACCTCCGTCATGTGCTGTGACTGCTTGT182
substitution in codonAGATGGCCATGGCGCGGACGCGGGTGCCGGGCGGGGGTGT
157 resulting in aGGAATCAACCCACAGCTGCACAGGGCAGGTCTTGGCCAG
change from valine toGCACCCGCGTCCGCGCC183
phenylalanine.GGCGCGGACGCGGGTGC184
In a family withTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAA185
Li-Fraumeni in whichCAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCA
noncancerous skinCCATCATCACACTGGAAGACTCCAGGTCAGGAGCCAC
fibroblasts fromGTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGG186
affected individualsATGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACAC
showed an unusualATGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAA
radiation-resistantCATGGGCGGCATGAACC187
phenotype, a pointGGTTCATGCCGCCCATG188
mutation in codon 245
of the P53 gene. A
change from GGC to
GAC predicted
substitution of aspartic
acid for glycine.
In 2 of 8 families withACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTG189
Li-FraumeniCATGGGCGGCATGAACCGGAGGCCCATCCTCACCATCATCA
syndrome, a mutationCACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACCC
in codon 248: a GGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGAT190
CGG-to-CAG changeGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGG
resulting in substi-AACTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGT
tution of glutamineCATGAACCGGAGGCCCA191
for arginine.TGGGCCTCCGGTTCATG192
In 9 members of anCCCTGACTTTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTC193
extended family withCCCTGCCCTCAACAAGATGTTTTGCCAACTGGCCAAGACCTG
Li-FraumeniCCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCC
syndrome, a germlineGGCGGGGGTGTGGAATCAACCCACAGCTGCACAGGGCAGGT194
mutation at codon 133CTTGGCCAGTTGGCAAAACATCTGTTGAGGGCAGGGGAGTA
(ATG-to-ACG),CTGTAGGAAGAGGAAGGAGACAGAGTTGAAAGTCAGGG
resulted in theCAACAAGATGTTTTGCC195
substitution ofGGCAAAACATCTTGTTG196
threonine for
methionine (M133T),
and completely
cosegregated with the
cancer syndrome.
In 1 pedigreeTCTTGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGG197
consistent with theGACGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGA
Li-FraumeniGAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGA
syndrome, a germlineTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCCCAG198
G-to-T transversion atGACAGGCACAAACACGCACCTCAAAGCTGTTCCGTCCCAGTA
codon 272 (valine toGATTACCACTACTCAGGATAGGAAAAGAGAAGCAAGA
leucine) was found.GCTTTGAGGTGCGTGTT199
AACACGCACCTCAAAGC200
A ser241-to-pheTTATCTCCTAGGTTGGCTCTGACTGTACCACCATCCACTACAA201
mutation due to aCTACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAG
TCC-to-TTC changeGCCCATCCTCACCATCATCACACTGGAAGACTCCAG
was found in a patientCTGGAGTCTTCCAGTGTGATGATGGTGAGGATGGGCCTCCG202
with hepatoblastomaGTTCATGCCGCCCATGCAGGAACTGTTACACATGTAGTTGTA
and multiple foci ofGTGGATGGTGGTACAGTCAGAGCCAACCTAGGAGATAA
osteosarcomaTAACAGTTCCTGCATGG203
CCATGCAGGAACTGTTA204
An AAG-to-TAGCAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTTC205
change of codon 120,TTGCATTCTGGGACAGCCAAGTCTGTGACTTGCACGGTCAGT
resulting in conversionTGCCCTGAGGGGCTGGCTTCCATGAGACTTCAATGCC
from lysine to a stopGGCATTGAAGTCTCATGGAAGCCAGCCCCTCAGGGCAACTG206
codon, was found in a ACCGTGCAAGTCACAGACTTGGCTGTCCCAGAATGCAAGAAG
patient withCCCAGACGGAAACCGTAGCTGCCCTGGTAGGTTTTCTG
osteosarcoma and GGACAGCCAAGTCTGTG207
adenocarcinoma ofCACAGACTTGGCTGTCC208
lung at age 18 and
brain tumor (glioma) at
the age of 27.
A CGG-to-TGGGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGT209
change at codon 282,GCCTGTCCTGGGAGAGACCGGCGCACAGAGGAAGAGAATCT
resulting in theCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAG
substitution ofCTGGGGGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGA210
tryptophan for argi-TTCTCTTCCTCTGTGCGCCGGTCTCTCCCAGGACAGGCACAA
nine, was found in aACACGCACCTCAAAGCTGTTCCGTCCCAGTAGATTACC
patient who developedGGAGAGACCGGCGCACA211
osteosarcoma at theTGTGCGCCGGTCTCTCC212
age of 10 years.
In 5 of 6 anaplasticGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACG213
carcinomas of theGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGAGA
thyroid and in anCCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGG
anaplastic carcinomaCCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTC214
thyroid cell line ARO,aCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTCCGTCCC
CGT-to-CAT mutationAGTAGATTACCACTACTCAGGATAGGAAAAGAGAAGC
convertedTGAGGTGCGTGTTTGTG215
arginine-273 toCACAAACACGCACCTCA216
histidine.
A germlineTCCTAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAA217
GGA-to-GTA mutationAGAAGAAACCACTGGATGGAGAATATTTCACCCTTCAGGTACT
resulting in a changeAAGTCTTGGGACCTCTTATCAAGTGGAAAGTTTCCA
ofTGGAAACTTTCCACTTGATAAGAGGTCCCAAGACTTAGTACCT218
glycine-325 to valineGAAGGGTGAAATATTCTCCATCCAGTGGTTTCTTCTTTGGCTG
was found in a patientGGGAGAGGAGCTGGTGTTGTTGGGCAGTGCTAGGA
who had non-HodgkinACTGGATGGAGAATATT219
lymphoma diagnosedAATATTCTCCATCCAGT220
at age 17 and colon
carcinoma at age 26.
CGC-CCCAATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAA221
Arg-72 to ProTGCCAGAGGCTGCTCCCCGCGTGGCCCCTGCACCAGCAGCT
association with LungCCTACACCGGCGGCCCCTGCACCAGCCCCCTCCTGGCC
cancerGGCCAGGAGGGGGCTGGTGCAGGGGCCGCCGGTGTAGGAG222
CTGCTGGTGCAGGGGCCACGCGGGGAGCAGCCTCTGGCATT
CTGGGAGCTTCATCTGGACCTGGGTCTTCAGTGAACCATT
TGCTCCCCGCGTGGCCC223
GGGCCACGCGGGGAGCA224
CCG-CTGAAGCTCCCAGAATGCCAGAGGCTGCTCCCCGCGTGGCCCCT225
Pro-82 to LeuGCACCAGCAGCTCCTACACCGGCGGCCCCTGCACCAGCCCC
Breast cancerCTCCTGGCCCCTGTCATCTTCTGTCCCTTCCCAGAAAAC
GTTTTCTGGGAAGGGACAGAAGATGACAGGGGCCAGGAGGG226
GGCTGGTGCAGGGGCCGCCGGTGTAGGAGCTGCTGGTGCA
GGGGCCACGCGGGGAGCAGCCTCTGGCATTCTGGGAGCTT
TCCTACACCGGCGGCCC227
GGGCCGCCGGTGTAGGA228
cCAA-TAATTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTCCCCTGCCC229
Gln-136 to TermTCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGC
Li-Fraumeni syndromeAGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCC
GGGTGCCGGGCGGGGGTGTGGAATCAACCCACAGCTGCACA230
GGGCAGGTCTTGGCCAGTTGGCAAAACATCTTGTTGAGGGCA
GGGGAGTACTGTAGGAAGAGGAAGGAGACAGAGTTGAA
TGTTTTGCCAACTGGCC231
GGCCAGTTGGCAAAACA232
TGC-TACTCCTCTTCCTACAGTACTCCCCTGCCCTCAACAAGATGTTTTG233
Cys-141 to TyrCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTC
Li-Fraumeni syndromeCACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGC
GCCATGGCGCGGACGCGGGTGCCGGGCGGGGGTGTGGAAT234
CAACCCACAGCTGCACAGGGCAGGTCTTGGCCAGTTGGCAA
AACATCTTGTTGAGGGCAGGGGAGTACTGTAGGAAGAGGA
CAAGACCTGCCCTGTGC235
GCACAGGGCAGGTCTTG236
aCCC-TCCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAG237
Pro-151 to SerCTGTGGGTTGATTCCACACCCCCGCCCGGCACCCGCGTCCG
Li-Fraumeni syndromeCGCCATGGCCATCTACAAGCAGTCACAGCACATGACGG
CCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCGCGG238
ACGCGGGTGCCGGGCGGGGGTGTGGAATCAACCCACAGCT
GCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCTTGTT
ATTCCACACCCCCGCCC239
GGGCGGGGGTGTGGAAT240
CCG-CTGAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGT241
Pro-152 to LeuGGGTTGATTCCACACCCCCGCCCGGCACCCGCGTCCGCGCC
AdrenocorticalATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGT
carcinomaACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCG242
CGGACGCGGGTGCCGGGCGGGGGTGTGGAATCAACCCACA
GCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCT
CACACCCCCGCCCGGCA243
TGCCGGGCGGGGGTGTG244
GGC-GTCTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTG245
Gly-154 to ValATTCCACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGCC
GlioblastomaATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAG
CTCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCC246
ATGGCGCGGACGCGGGTGCCGGGCGGGGGTGTGGAATCAA
CCCACAGCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAA
CCCGCCCGGCACCCGCG247
CGCGGGTGCCGGGCGGG248
CGC-CACCCCGCGTCCGCGCCATGGCCATCTACAAGCAGTCACAGCAC249
Arg-175 to HisATGACGGAGGTTGTGAGGCGCTGCCCCCACCATGAGCGCTG
Li-Fraumeni syndromeCTCAGATAGCGATGGTGAGCAGCTGGGGCTGGAGAGACG
CGTCTCTCCAGCCCCAGCTGCTCACCATCGCTATCTGAGCAG250
CGCTCATGGTGGGGGCAGCGCCTCACAACCTCCGTCATGTG
CTGTGACTGCTTGTAGATGGCCATGGCGCGGACGCGGG
TGTGAGGCGCTGCCCCC251
GGGGGCAGCGCCTCACA252
tGAG-AAGATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTG253
Glu-180 to LysAGGCGCTGCCCCCACCATGAGCGCTGCTCAGATAGCGATGG
Li-Fraumeni syndromeTGAGCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGC
GCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCACCAT254
CGCTATCTGAGCAGCGCTCATGGTGGGGGCAGCGCCTCACA
ACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCAT
CCCACCATGAGCGCTGC255
GCAGCGCTCATGGTGGG256
gCGC-TGCGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGG257
Arg-181 to CysCGCTGCCCCCACCATGAGCGCTGCTCAGATAGCGATGGTGA
Breast cancerGCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCA
TGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCA258
CCATCGCTATCTGAGCAGCGCTCATGGTGGGGGCAGCGCCT
CACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGC
ACCATGAGCGCTGCTCA259
TGAGCAGCGCTCATGGT260
CGC-CACCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGGC261
Arg-81 to HisGCTGCCCCCACCATGAGCGCTGCTCAGATAGCGATGGTGAG
Breast cancerCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCAG
CTGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTC262
ACCATCGCTATCTGAGCAGCGCTCATGGTGGGGGCAGCGCC
TCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGG
CCATGAGCGCTGCTCAG263
CTGAGCAGCGCTCATGG264
CAT-CGTCCAGGGTCCCCAGGCCTCTGATTCCTCACTGATTGCTCTTAG265
His-193 to ArgGTCTGGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATT
Li-Fraumeni syndromeTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCG
CGAAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAATTTC266
CTTCCACTCGGATAAGATGCTGAGGAGGGGCCAGACCTAAGA
GCAATCAGTGAGGAATCAGAGGCCTGGGGACCCTGG
TCCTCAGCATCTTATCC267
GGATAAGATGCTGAGGA268
cCGA-TGACCCAGGCCTCTGATTCCTCACTGATTGCTCTTAGGTCTGGCC269
Arg-196 to TermCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGTGTG
AdrenocorticalGAGTATTTGGATGACAGAAACACTTTTCGACATAGTG
carcinomaCACTATGTCGAAAAGTGTTTCTGTCATCCAAATACTCCACACG270
CAAATTTCCTTCCACTCGGATAAGATGCTGAGGAGGGGCCAG
ACCTAAGAGCAATCAGTGAGGAATCAGAGGCCTGGG
ATCTTATCCGAGTGGAA271
TTCCACTCGGATAAGAT272
cAGA-TGAGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGT273
Arg-209 to TermGTGGAGTATTTGGATGACAGAAACACTTTTCGACATAGTGTG
Li-Fraumeni syndromeGTGGTGCCCTATGAGCCGCCTGAGGTCTGGTTTGCAA
TTGCAAACCAGACCTCAGGCGGCTCATAGGGCACCACCACA274
CTATGTCGAAAAGTGTTTCTGTCATCCAAATACTCCACACGCA
AATTTCCTTCCACTCGGATAAGATGCTGAGGAGGGGC
TGGATGACAGAAACACT275
AGTGTTTCTGTCATCCA276
tCGA-TGACATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTG277
Arg-213 to TermGATGACAGAAACACTTTTCGACATAGTGTGGTGGTGCCCTAT
Li-Fraumeni syndromeGAGCCGCCTGAGGTCTGGTTTGCAACTGGGGTCTCTG
CAGAGACCCCAGTTGCAAACCAGACCTCAGGCGGCTCATAG278
GGCACCACCACACTATGTCGAAAAGTGTTTCTGTCATCCAAAT
ACTCCACACGCAAATTTCCTTCCACTCGGATAAGATG
ACACTTTTCGACATAGT279
ACTATGTCGAAAAGTGT280
gCCC-TCCGGAAATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTC281
Pro-219 to SerGACATAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTCTGG
AdrenocorticalTTTGCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGT
carcinomaACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAACCAGA282
CCTCAGGCGGCTCATAGGGCACCACCACACTATGTCGAAAAG
TGTTTCTGTCATCCAAATACTCCACACGCAAATTTCC
TGGTGGTGCCCTATGAG283
CTCATAGGGCACCACCA284
TAT-TGTATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGACA285
Tyr-220 to CysTAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTCTGGTTTG
Li-Fraumeni syndromeCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGTGGTT
AACCACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAAC286
CAGACCTCAGGCGGCTCATAGGGCACCACCACACTATGTCG
AAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAAT
GGTGCCCTATGAGCCGC287
GCGGCTCATAGGGCACC288
cTCT-ACTCACAGGTCTCCCCAAGGCGCACTGGCCTCATCTTGGGCCTG289
Ser-227 to ThrTGTTATCTCCTAGGTTGGCTCTGACTGTACCACCATCCACTAC
RhabdomyosarcomaAACTACATGTGTAACAGTTCCTGCATGGGCGGCATGA
TCATGCCGCCCATGCAGGAACTGTTACACATGTAGTTGTAGT290
GGATGGTGGTACAGTCAGAGCCAACCTAGGAGATAACACAG
GCCCAAGATGAGGCCAGTGCGCCTTGGGGAGACCTGTG
AGGTTGGCTCTGACTGT291
ACAGTCAGAGCCAACCT292
cCAC-AACGCACTGGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGC293
His-233 to AsnTCTGACTGTACCACCATCCACTACAACTACATGTGTAACAGTT
GliomaCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCA
TGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTG294
TTACACATGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCA
ACCTAGGAGATAACACAGGCCCAAGATGAGGCCAGTGC
CCACCATCCACTACAAC295
GTTGTAGTGGATGGTGG296
cAAC-GACGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGAC297
Asn-235 to AspTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCA
AdrenocorticalTGGGCGGCATGAACCGGAGGCCCATCCTCACCATCA
carcinomaTGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAG298
GAACTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGTCA
GAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGGC
TCCACTACAACTACATG299
CATGTAGTTGTAGTGGA300
AAC-AGCCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGACT301
Asn-235 to SerGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCAT
RhabdomyosarcomaGGGCGGCATGAACCGGAGGCCCATCCTCACCATCAT
ATGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCA302
GGAACTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGTC
AGAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGG
CCACTACAACTACATGT303
ACATGTAGTTGTAGTGG304
ATCc-ATGCATCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGG305
Ile-251 to MetCATGAACCGGAGGCCCATCCTCACCATCATCACACTGGAAGA
GliomaCTCCAGGTCAGGAGCCACTTGCCACCCTGCACACTGG
CCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTT306
CCAGTGTGATGATGGTGAGGATGGGCCTCCGGTTCATGCCG
CCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGATG
AGGCCCATCCTCACCAT307
ATGGTGAGGATGGGCCT308
ACA-ATAACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGG309
Thr-256 to IleCCCATCCTCACCATCATCACACTGGAAGACTCCAGGTCAGGA
GlioblastomaGCCACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCA
TGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGGCTCC310
TGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGATGGGCCT
CCGGTTCATGCCGCCCATGCAGGAACTGTTACACATGT
CATCATCACACTGGAAG311
CTTCCAGTGTGATGATG312
CTG-CAGTGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCC313
Leu-257 to GlnATCCTCACCATCATCACACTGGAAGACTCCAGGTCAGGAGCC
Li-Fraumeni syndromeACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCC
GGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGG314
CTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGATGG
GCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACACA
CATCACACTGGAAGACT315
AGTCTTCCAGTGTGATG316
CTG-GCGGACCTGATTTCCTTACTGCCTCTTGCTTCTCTTTTCCTATCCT317
Leu-265 to ProGAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCG
Li-Fraumeni syndromeTGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGA
TCTGTGCGCCGGTCTCTCCCAGGACAGGCACAAACACGCAC318
CTCAAAGCTGTTCCGTCCCAGTAGATTACCACTACTCAGGAT
AGGAAAAGAGAAGCAAGAGGCAGTAAGGAAATCAGGTC
TAATCTACTGGGACGGA319
TCCGTCCCAGTAGATTA320
gCGT-TGTTGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGAC321
Arg-273 to CysGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGA
Li-Fraumeni syndromeGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAG
CTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCC322
CAGGACAGGCACAAACACGCACCTCAAAGCTGTTCCGTCCCA
GTAGATTACCACTACTCAGGATAGGAAAAGAGAAGCA
TTGAGGTGCGTGTTTGT323
ACAAACACGCACCTCAA324
TGT-TATCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACGGAACA325
Cys-275 to TyrGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGAGACCGG
Li-Fraumeni syndromeCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCC
GGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGG326
TCTCTCCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTC
CGTCCCAGTAGATTACCACTACTCAGGATAGGAAAAG
GCGTGTTTGTGCCTGTC327
GACAGGCACAAACACGC328
CCT-CTTTCCTGAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGG329
Pro-278 to LeuTGCGTGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGAG
Breast cancerGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGA
TCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCT330
GTGCGCCGGTCTCTCCCAGGACAGGCACAAACACGCACCTC
AAAGCTGTTCCGTCCCAGTAGATTACCACTACTCAGGA
TGCCTGTCCTGGGAGAG331
CTCTCCCAGGACAGGCA332
AGA-AAAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTG333
Arg-280 to LysTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGAGGAAGAG
GliomaAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCC
GGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCT334
TCCTCTGTGCGCCGGTCTCTCCCAGGACAGGCACAAACACG
CACCTCAAAGCTGTTCCGTCCCAGTAGATTACCACTAC
TCCTGGGAGAGACCGGC335
GCCGGTCTCTCCCAGGA336
GAA-GCAGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGA337
Glu-286 to AlaGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGA
AdrenocorticalGCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGG
carcinomaCCTCGCTTAGTGCTCCCTGGGGGCAGCTCGTGGTGAGGCTC338
CCCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCT
CCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTCC
AGAGGAAGAGAATCTCC339
GGAGATTCTCTTCCTCT340
CGA-CCAAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTG341
Arg-306 to ProCCCCCAGGGAGCACTAAGCGAGGTAAGCAAGCAGGACAAGA
RhabdomyosarcomaAGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGAT
ATCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCT342
TGTCCTGCTTGCTTACCTCGCTTAGTGCTCCCTGGGGGCAGC
TCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTT
CACTAAGCGAGGTAAGC343
GCTTACCTCGCTTAGTG344
gCGA-TGAGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCT345
Arg-306 to TermGCCCCCAGGGAGCACTAAGCGAGGTAAGCAAGCAGGACAAG
Li-Fraumeni syndromeAAGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGA
TCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCTT346
GTCCTGCTTGCTTACCTCGCTTAGTGCTCCCTGGGGGCAGCT
CGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTC
GCACTAAGCGAGGTAAG347
CTTACCTCGCTTAGTGC348
gCGC-TGCGGTACTGTGAATATACTTACTTCTCCCCCTCCTCTGTTGCTGC349
Arg-337 to CysAGATCCGTGGGCGTGAGCGCTTCGAGATGTTCCGAGAGCTG
OsteosarcomaAATGAGGCCTTGGAACTCAAGGATGCCCAGGCTGGGA
TCCCAGCCTGGGCATCCTTGAGTTCCAAGGCCTCATTCAGCT350
CTCGGAACATCTCGAAGCGCTCACGCCCACGGATCTGCAGC
AACAGAGGAGGGGGAGAAGTAAGTATATTCACAGTACC
GGCGTGAGCGCTTCGAG351
CTCGAAGCGCTCACGCC352
CTG-CCGCTCCCCCTCCTCTGTTGCTGCAGATCCGTGGGCGTGAGCGC353
Leu-344 to ProTTCGAGATGTTCCGAGAGCTGAATGAGGCCTTGGAACTCAAG
Li-Fraumeni syndromeGATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGC
GCCCTGCTCCCCCCTGGCTCCTTCCCAGCCTGGGCATCCTT354
GAGTTCCAAGGCCTCATTCAGCTCTCGGAACATCTCGAAGCG
CTCACGCCCACGGATCTGCAGCAACAGAGGAGGGGGAG
CCGAGAGCTGAATGAGG355
CCTCATTCAGCTCTCGG356
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Beta Globin
[0115] Hemoglobin, the major protein in the red blood cell, binds oxygen reversibly and is responsible for the cells' capacity to transport oxygen to the tissues. In adults, the major hemoglobin is hemoglobin A, a tetrameric protein consisting of two identical alpha globin chains and two beta globin chains. Disorders involving hemoglobin are among the most common genetic disorders worldwide, with approximately 5% of the world's population being carriers for clinically important hemoglobin mutations. Approximately 300,000 severely affected homozygotes or compound heterozygotes are born each year.
[0116] Mutation of the glutamic acid at position 7 in beta globin to valine causes sickle cell anemia, the clinical manifestations of which are well known. Mutations that cause absence of beta chain cause beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia.
[0117] For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic). Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl.
[0118] The beta-thalassemias were among the first human genetic diseases to be examined by means of recombinant DNA analysis. Baysal et al., Hemoglobin 19(3-4):213-36 (1995) and others provide a compendium of mutations that result in beta-thalassemia.
[0119] Hemoglobin disorders were among the first to be considered for gene therapy. Transcriptional silencing of genes transferred into hematopoietic stem cells, however, poses one of the most significant challenges to its success. If the transferred gene is not completely silenced, a progressive decline in gene expression is often observed. Position effect variegation (PEV) and silencing mechanisms may act on a transferred globin gene residing in chromatin outside of the normal globin locus during the important terminal phases of erythroblast development when globin transcripts normally accumulate rapidly despite heterochromatization and shutdown of the rest of the genome. The attached table discloses the correcting oligonucleotide base sequences for the beta globin oligonucleotides of the invention.
13TABLE 12
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Beta Globin Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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Sickle Cell AnemiaTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCA357
GLU-7-VALTGGTGCACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCC
GAG to GTGCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGA
TCACCACCAACTTCATCCACGTTCACCTTGCCCCACAGGGCA358
GTAACGGCAGACTTCTCCTCAGGAGTCAGGTGCACCATGGT
GTCTGTTTGAGGTTGCTAGTGAACACAGTTGTGTCAGA
GACTCCTGAGGAGAAGT359
ACTTCTCCTCAGGAGTC360
Thalassaemia BetaCTATTGCTTACTTTGCTTCTGACACAACTGTGTTCACTAGCA361
MET-0-ARGACCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGA
ATG to AGGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT
ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC362
CTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAGGTTGCT
AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG
AGACACCATGGTGCACC363
GGTGCACCATGGTGTCT364
Thalassaemia BetaTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA365
MET-0-ILECCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAA
ATG to ATAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTG
CACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT366
CCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAGGTTGC
TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA
GACACCATGGTGCACCT367
AGGTGCACCATGGTGTC368
Thalassaemia BetaTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA369
MET-0-ILECCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGACAA
ATG to ATTGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTG
CACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT370
CCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAGGTTGC
TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA
GACACCATGGTGCACCT371
AGGTGCACCATGGTGTC372
Thalassaemia BetaCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA373
MET-0-LYSACCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGA
ATG to AAGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT
ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC374
CTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAGGTTGCT
AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG
AGACACCATGGTGCACC375
GGTGCACCATGGTGTCT376
Thalassaemia BetaCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA377
MET-0-THRACCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGA
ATG to ACGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT
ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC378
CTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAGGTTGCT
AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG
AGACACCATGGTGCACC379
GGTGCACCATGGTGTCT380
Thalassaemia BetaTCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGC381
MET-0-VALAACCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAG
ATG to GTGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACG
CGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTCC382
TCAGGAGTCAGGTGCACCATGGTGTCTGTTTTGAGGTTGCTAG
TGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAGA
CAGACACCATGGTGCAC383
GTGCACCATGGTGTCTG384
Thalassaemia BetaTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGT385
TRP-16-TermCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAA
TGG to TGAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTA
TAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTC386
ATCCACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACT
TCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGA
GCCCTGTGGGGCAAGGT387
ACCTTGCCCCACAGGGC388
Thalassaemia BetaCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAG389
TRP-16-TermTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGA
TGG to TAG AGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTT
AACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTCA390
TCCACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTT
CTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAG
TGCCCTGTGGGGCAAGG391
CCTTGCCCCACAGGGCA392
Thalassaemia BetaACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGTCTGC393
LYS-18-TermCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTG
AAG to TAG GTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTACAAG
CTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAA394
CTTCATCCACGTTCACCTTGCCCCACAGGGCAGTAACGGCA
GACTTCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGT
TGTGGGGCAAGGTGAAC395
GTTCACCTTGCCCCACA396
Thalassaemia BetaCCATGGTGCACCTGACTCCTGAGGAGAAGTCTGCCGTTACT397
ASN-20-SERGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGA
AAC to AGCGGCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTT
AACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCA398
CCACCAACTTCATCCACGTTCACCTTGCCCCACAGGGCAGTA
ACGGCAGACTTCTCCTCAGGAGTCAGGTGCACCATGG
CAAGGTGAACGTGGATG399
CATCCACGTTCACCTTG400
Thalassaemia BetaACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGG401
GLU-23-ALAGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTGG
GAA to GCAGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGAC
GTCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCC402
AGGGCCTCACCACCAACTTCATCCACGTTCACCTTGCCCCAC
AGGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGT
CGTGGATGAAGTTGGTG403
CACCAACTTCATCCACG404
Thalassaemia BetaCACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTG405
GLU-23-termGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAGGCCCTG
GAA to TAAGGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGA
TCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCCA406
GGGCCTCACCACCAACTTCATCCACGTTCACCTTGCCCCACA
GGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGTG
ACGTGGATGAAGTTGGT407
ACCAACTTCATCCACGT408
Thalassaemia BetaGAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA409
GLU-27-LYSCGTGGATGCAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTAT
GAG to AAGCAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACT
AGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC410
CAACCTGCCCAGGGCCTCACCACCAACTGCATCCACGTTCA
CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC
TTGGTGGTGAGGCCCTG411
CAGGGCCTCACCACCAA412
Thalassaemia BetaGAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA413
GLU-27-TermCGTGGATGCAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTAT
GAG to TAGCAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACT
AGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC414
CAACCTGCCCAGGGCCTCACCACCAACTGCATCCACGTTCA
CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC
TTGGTGGTGAGGCCCTG415
CAGGGCCTCACCACCAA416
Thalassaemia BetaGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAACGT417
ALA-28-SERGGATGCAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAA
GCC to TCCGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACTGGG
CCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGA418
TACCAACCTGCCCAGGGCCTCACCACCAACTGCATCCACGT
TCACTTTGCCCCACAGGGCATTGACAGCAGTCTTCTC
GTGGTGAGGCCCTGGGC419
GCCCAGGGCCTCACCAC420
Thalassaemia BetaCTGTCAATGCCCTGTGGGGCAAAGTGAACGTGGATGCAGTT421
ARG-31-THRGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTATAAGA
AGG to ACGGAGGCTCAAGGAGGCAAATGGAAACTGGGCATGTGTAGA
TCTACACATGCCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTT422
ATAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTG
CATCCACGTTCACTTTGCCCCACAGGGCATTGACAG
CCTGGGCAGGTTGGTAT423
ATACCAACCTGCCCAGG424
Thalassaemia BetaTGGGTTTCTGATAGGCACTGACTCTCTGTCCCTTGGGCTGTT425
Leu-33-GLNTTCCTACCCTCAGATTACTGGTGGTCTACCCTTGGACCCAGA
CTG to GAGGGTTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGA
TCAGGAGAGGACAGATCCCCAAAGGACTCAAAGAACCTCTG426
GGTCCAAGGGTAGACCACCAGTAATCTGAGGGTAGGAAAAC
AGCCCAAGGGACAGAGAGTCAGTGCCTATCAGAAACCCA
CAGATTACTGGTGGTCT427
AGACCACCAGTAATCTG428
Thalassaemia BetaATAGGCACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCT429
TYR-36-TermCAGATTACTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGA
TAC to TAAGTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTATG
CATAACAGCATCAGGAGAGGACAGATCCCCAAAGGACTCAAA430
GAACCTCTGGGTCCAAGGGTAGACCACCAGTAATCTGAGGG
TAGGAAAACAGCCCAAGGGACAGAGAGTCAGTGCCTAT
GTGGTCTACCCTTGGAC431
GTCCAAGGGTAGACCAC432
Thalassaemia BetaACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATT433
TRP-38-TermACTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTT
TGG to TGATGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAAC
GTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGG434
ACTCAAAGAACCTCTGGGTCCAAGGGTAGACCACCAGTAATC
TGAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGT
TACCCTTGGACCCAGAG435
CTCTGGGTCCAAGGGTA436
Thalassaemia BetaCACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGAT437
TRP-38-TermTACTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCT
TGG to TAGTTGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAA
TTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGGA438
CTCAAAGAACCTCTGGGTCCAAGGGTAGACCACCAGTAATCT
GAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGTG
CTACCCTTGGACCCAGA439
TCTGGGTCCAAGGGTAG440
Thalassaemia BetaACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATTACTG441
GLN-40-TermGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGG
CAG-TAGGATCTGTCCTCTCCTGATGCTGTTATGGGCAACCCTA
TAGGGTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCA442
AAGGACTCAAAGAACCTCTGGGTCCAAGGGTAGACCACCAG
TAATCTGAGGGTAGGAAAACAGCCCAAGGGACAGAGAGT
CTTGGACCCAGAGGTTC443
GAACCTCTGGGTCCAAG444
Thalassaemia BetaTTGGGCTGTTTTCCTACCCTCAGATTACTGGTGGTCTACCCT445
GLU-44-TermTGGACCCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCTCT
GAG to TAGCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTC
GAGCCTTCACCTTAGGGTTGCCCATAACAGCATCAGGAGAG446
GACAGATCCCCAAAGGACTCAAAGAACCTCTGGGTCCAAGG
GTAGACCACCAGTAATCTGAGGGTAGGAAAACAGCCCAA
GGTTCTTTGAGTCCTTT447
AAAGGACTCAAAGAACC448
Thalassaemia BetaTTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTA449
LYS-62-TermTGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAGGTGCTA
AAG to TAGGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACC
GGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGCACCTAGC450
ACCTTCTTGCCATGAGCCTTCACCTTAGGGTTGCCCATAACA
GCATCAGGAGAGGACAGATCCCCAAAGGACTCAAAGAA
CTAAGGTGAAGGCTCAT451
ATGAGCCTTCACCTTAG452
Thalassaemia BetaTGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGA453
SER-73-ARGAGGTGCTAGGTGCCTTTAGTGATGGCCTGGCTCACCTGGAC
AGT to AGAAACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCAC
GTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTC454
CAGGTGAGCCAGGCCATCACTAAAGGCACCTAGCACCTTCT
TGCCATGAGCCTTCACCTTAGGGTTGCCCATAACAGCA
GCCTTTAGTGATGGCCT455
AGGCCATCACTAAAGGC456
Haemolytic AnaemiaTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAGGTG457
GLY-75-VALCTAGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCT
GGC to GTCCAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCACTGTGA
TCACAGTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAG458
GTTGTCCAGGTGAGCCAGGCCATCACTAAAGGCACCTAGCA
CCTTCTTGCCATGAGCCTTCACCTTAGGGTTGCCCATAA
TAGTGATGGCCTGGCTC459
GAGCCAGGCCATCACTA460
Thalassaemia BetaGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGG461
GLU-91-TermCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGC
GAG to TAGACGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACC
GGTCCCATAGACTCACCCTGAAGTTCTCAGGATCCACGTGCA462
GCTTGTCACAGTGCAGCTCACTCAGTGTGGCAAAGGTGCCC
TTGAGGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGC
CACTGAGTGAGCTGCAC463
GTGCAGCTCACTCAGTG464
Thalassaemia BetaCTGGACAACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTG465
VAL-99-METCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGGT
GTG to ATGGAGTCCAGGAGATGCTTCACTTTTCTCTTTTTACTTTC
GAAAGTAAAAAGAGAAAAGTGAAGCATCTCCTGGACTCACCC466
TGAAGTTCTCAGGATCCACGTGCAGCTTGTCACAGTGCAGCT
CACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTCCAG
AGCTGCACGTGGATCCT467
AGGATCCACGTGCAGCT468
Thalassaemia BetaCCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCCCACA469
LEU-111-PROGCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACT
CTG-CCGTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTA
TAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTG470
ATGGGCCAGCACACAGACCAGCACGTTGCCCAGGAGCTGTG
GGAGGAAGATAAGAGGTATGAACATGATTAGCAAAAGGG
CAACGTGCTGGTCTGTG471
CACAGACCAGCACGTTG472
Thalassaemia BetaGCTAATCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTG473
CYS-113-TermGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAA
TGT to TGAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAA
TTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCC474
AAAGTGATGGGCCAGCACACAGACCAGCACGTTGCCCAGGA
GCTGTGGGAGGAAGATAAGAGGTATGAACATGATTAGC
CTGGTCTGTGTGCTGGC475
GCCAGCACACAGACCAG476
Thalassaemia BetaTCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCA477
LEU-115-PROACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAAT
CTG to CCGTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGT
ACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCT478
TTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCC
CAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACATGA
CTGTGTGCTGGCCCATC479
GATGGGCCAGCACACAG480
Thalassaemia BetaTGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCAACG481
ALA-116-ASPTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCA
GCC to GACCCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGC
GCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAA482
TTCTTTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTT
GCCCAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACA
TGTGCTGGCCCATCACT483
AGTGATGGGCCAGCACA484
Thalassaemia BetaTTCCTCCCACAGCTCCTGGGCAACGTGCTGGTCTGTGTGCT485
GLU-122-TermGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGG
GAA to TAACTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCC
GGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCC486
TGCACTGGTGGGGTGAATTCTTTGCCAAAGTGATGGGCCAG
CACACAGACCAGCACGTTGCCCAGGAGCTGTGGGAGGAA
TTGGCAAAGAATTCACC487
GGTGAATTCTTTGCCAA488
Thalassaemia BetaGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAA489
GLN-128-PROGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGT
CVAG to CCGGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTA
TAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCAC490
CACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTT
GCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGC
ACCAGTGCAGGCTGCCT491
AGGCAGCCTGCACTGGT492
Thalassaemia BetaGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAA493
GLN-128-TermAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGT
CAG to TAGGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACT
AGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACC494
ACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTG
CCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCC
CACCAGTGCAGGCTGCC495
GGCAGCCTGCACTGGTG496
Thalassaemia BetaGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCA497
GLN-132-LYSCCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGC
GAG to AAGTAATGCCCTGGCCCACAAGTATCACTAAGCTCGCTTTC
GAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCC498
ACACCAGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGG
GGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGAC
CTGCCTATCAGAAAGTG499
CACTTTCTGATAGGCAG500
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Retinoblastoma
[0120] Retinoblastoma (RB) is an embryonic neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. The risk of osteogenic sarcoma is increased 500-fold in bilateral retinoblastoma patents, the bone malignancy being at sites removed from those exposed to radiation treatment of the eye tumor.
[0121] The retinoblastoma susceptibility gene (pRB; pRb) plays a pivotal role in the regulation of the cell cycle. pRB restrains cell cycle progression by maintaining a checkpoint in late G1 that controls commitment of cells to enter S phase. The critical role that pRB plays in cell cycle regulation explains its status as archetypal tumor suppressor: loss of pRB function results in an inability to maintain control of the G1 checkpoint; unchecked progression through the cell cycle is, in turn, a hallmark of neoplasia.
[0122] Blanquet et al., Hum. Molec. Genet. 4: 383-388 (1995) performed a mutation survey of the RB1 gene in 232 patents with hereditary or nonhereditary retinoblastoma. They systematically explored all 27 exons and flanking sequences, as well as the promoter. All types of point mutations were represented and found to be unequally distributed along the RB1 gene sequence. In the population studied, exons 3, 8, 18, and 19 were preferentially altered. The attached table discloses the correcting oligonucleotide base sequences for the retinoblastoma oligonucleotides of the invention.
14TABLE 13
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pRB Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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RetinoblastomaAATATTTGATCTTTATTTTTTGTTCCCAGGGAGGTTATATTCAA501
Trp99TermAAGAAAAAGGAACTGTGGGGAATCTGTATCTTTATTGCAGCA
TGG-TAGGTTGACCTAGATGAGATGTCGTTCACTTTTACTGA
TCAGTAAAAGTGAACGACATCTCATCTAGGTCAACTGCTGCA502
ATAAAGATACAGATTCCCCACAGTTCCTTTTTCTTTTGAATATA
ACCTCCCTGGGAACAAAAAATAAAGATCAAATATT
GGAACTGTGGGGAATCT503
AGATTCCCCACAGTTCC504
RetinoblastomaATTTACTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATTCTT505
Glu137AspTAACTTACTAAAAGAAATTGATACCAGTACCAAAGTTGATAAT
GAA-GATGCTATGTCAAGACTGTTGAAGAAGTATGATGTA
TACATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTT506
TGGTACTGGTATCAATTTCTTTTAGTAAGTTAAAGAATTTATGG
ACACTACAAAGGAAAGAATAGAAAAAAGTAAAT
CTAAAAGAAATTGATAC507
GTATCAATTTCTTTTAG508
RetinoblastomaTGATTTACTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATT509
Glu137TermCTTTAACTTACTAAAAGAAATTGATACCAGTACCAAAGTTGAT
GAA-TAAAATGCTATGTCAAGACTGTTGAAGAAGTATGATG
CATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTTT510
GGTACTGGTATCAATTTCTTTTAGTAAGTTAAAGAATTTATGG
ACACTACAAAGGAAAGAATAGAAAAAAGTAAATCA
TACTAAAAGAAATTGAT511
ATCAATTTCTTTTAGTA512
RetinoblastomaAAAATGTTAAAAAGTCATAATGTTTTTCTTTTCAGGACATGTGA513
Gln176TermACTTATATATTTGACACAACCCAGCAGTTCGTAAGTAGTTCAC
CAA-TAAAGAATGTTATTTTTCACTTAAAAAAAAAGATTTT
AAAATCTTTTTTTTTAAGTGAAAAATAACATTCTGTGAACTACT514
TACGAACTGCTGGGTTGTGTCAAATATATAAGTTCACATGTCC
TGAAAAGAAAAACATTATGACTTTTTAACATTTT
ATTTGACACAACCCAGC515
GCTGGGTTGTGTCAAAT516
RetinoblastomaTGATACATTTTTCCTGTTTTTTTTCTGCTTTCTATTTGTTTAATA517
Ile185ThrGGATATCTACTGAAATAAATTCTGCATTGGTGCTAAAAGTTTC
ATA-ACATTGGATCACATTTTTATTAGCTAAAGGTAAGTT
AACTTACCTTTAGCTAATAAAAATGTGATCCAAGAAACTTTTA518
GCACCAATGCAGAATTTATTTCAGTAGATATCCTATTAAACAA
ATAGAAAGCAGAAAAAAAACAGGAAAAATGTATCA
TACTGAAATAAATTCTG519
CAGAATTTATTTCAGTA520
RetinoblastomaAAAGATCTGAATCTCTAACTTTCTTTAAAAATGTACATTTTTTT521
Gln207TermTTCAGGGGAAGTATTACAAATGGAAGATGATCTGGTGATTTC
CAA-TAAATTTCAGTTAATGCTATGTGTCCTTGACTATTTTA
TAAAATAGTCAAGGACACATAGCATTAACTGAAATGAAATCAC522
CAGATCATCTTCCATTTGTAATACTTCCCCTGAAAAAAAAATG
TACATTTTTAAAGAAAGTTAGAGATTCAGATCTTT
AAGTATTACAAATGGAA523
TTCCATTTGTAATACTT524
RetinoblastomaGTTCTTATCTAATTTACCACTTTTACAGAAACAGCTGTTATACC525
Arg251TermCATTAATGGTTCACCTCGAACACCCAGGCGAGGTCAGAACA
CGA to TGAGGAGTGCACGGATAGCAAAACAACTAGAAAATGATA
TATCATTTTCTAGTTGTTTTGCTATCCGTGCACTCCTGTTCTG526
ACCTCGCCTGGGTGTTCGAGGTGAACCATTAATGGGTATAAC
AGCTGTTTCTGTAAAAGTGGTAAATTAGATAAGAAC
GTTCACCTCGAACACCC527
GGGTGTTCGAGGTGAAC528
RetinoblastomaTTTACCACTTTTACAGAAACAGCTGTTATACCCATTAATGGTT529
Arg255TermCACCTCGAACACCCAGGCGAGGTCAGAACAGGAGTGCACG
CGA to TGAGATAGCAAAACAACTAGAAAATGATACAAGAATTATTG
CAATAATTCTTGTATCATTTTCTAGTTGTTTTGCTATCCGTGCA530
CTCCTGTTCTGACCTCGCCTGGGTGTTCGAGGTGAACCATTA
ATGGGTATAACAGCTGTTTCTGTAAAAGTGGTAAA
CACCCAGGCGAGGTCAG531
CTGACCTCGCCTGGGTG532
RetinoblastomaATTAATGGTTCACCTCGAACACCCAGGCGAGGTCAGAACAG533
Gln266TermGAGTGCACGGATAGCAAAACAACTAGAAAATGATACAAGAAT
CAA to TAATATTGAAGTTCTCTGTAAAGAACATGAATGTAATATAG
CTATATTACATTCATGTTCTTTACAGAGAACTTCAATAATTCTT534
GTATCATTTTCTAGTTGTTTTGCTATCCGTGCACTCCTGTTCT
GACCTCGCCTGGGTGTTCGAGGTGAACCATTAAT
TAGCAAAACAACTAGAA535
TTCTAGTTGTTTTGCTA536
RetinoblastomaTGACATGTAAAGGATAATTGTCAGTGACTTTTTTCTTTCAAGG537
Arg320TermTTGAAAATCTTTCTAAACGATACGAAGAAATTTATCTTAAAAAT
CGA to TGAAAAGATCTAGATGCAAGATTATTTTTGGATCATG
CATGATCCAAAAATAATCTTGCATCTAGATCTTTATTTTTAAGA538
TAAATTTCTTCGTATCGTTTAGAAAGATTTTCAACCTTGAAAGA
AAAAAGTCACTGACAATTATCCTTTACATGTCA
TTTCTAAACGATACGAA539
TTCGTATCGTTTAGAAA540
RetinoblastomaACAAATTGTAAATTTTCAGTATGTGAATGACTTCACTTATTGTT541
Gln354TermATTTAGTTTTGAAACACAGAGAACACCACGAAAAAGTAACCTT
CAG to TAGGATGAAGAGGTGAATGTAATTCCTCCACACACTC
GAGTGTGTGGAGGAATTACATTCACCTCTTCATCAAGGTTAC542
TTTTTCGTGGTGTTCTCTGTGTTTCAAAACTAAATAACAATAA
GTGAAGTCATTCACATACTGAAAATTTACAATTTGT
TTGAAACACAGAGAACA543
TGTTCTCTGTGTTTCAA544
RetinoblastomaTTTTCAGTATGTGAATGACTTCACTTATTGTTATTTAGTTTTGA545
Arg358GlyAACACAGAGAACACCACGAAAAAGTAACCTTGATGAAGAGGT
CGA to GGAGAATGTAATTCCTCCACACACTCCAGTTAGGTATG
CATACCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT546
CATCAAGGTTACTTTTTCGTGGTGTTCTCTGTGTTTCAAAACT
AAATAACAATAAGTGAAGTCATTCACATACTGAAAA
GAACACCACGAAAAAGT547
ACTTTTTCGTGGTGTTC548
RetinoblastomaTTTTCAGTATGTGAATGACTTCACTTATTGTTATTTAGTTTTGA549
Arg358TermAACACAGAGAACACCACGAAAAAGTAACCTTGATGAAGAGGT
CGA to TGAGAATGTAATTCCTCCACACACTCCAGTTAGGTATG
CATACCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT550
CATCAAGGTTACTTTTTCGTGGTGTTCTCTGTGTTTCAAAACT
AAATAACAATAAGTGAAGTCATTCACATACTGAAAA
GAACACCACGAAAAAGT551
ACTTTTTCGTGGTGTTC552
RetinoblastomaCTGTTATGAACACTATCCAACAATTAATGATGATTTTAAATTCA553
Ser397TermGCAAGTGATCAACCTTCAGAAAATCTGATTTCCTATTTTAACG
TCA to TAATAAGCCATATATGAAACATTATTTATTGTAATAT
ATATTACAATAAATAATGTTTCATATATGGCTTACGTTAAAATA554
GGAAATCAGATTTTCTGAAGGTTGATCACTTGCTGAATTTAAA
ATCATCATTAATTGTTGGATAGTGTTCATAACAG
TCAACCTTCAGAAAATC555
GATTTTCTGAAGGTTGA556
RetinoblastomaTTTCATAATTGTGATTTTCTAAAATAGCAGGCTCTTATTTTTCT557
Arg445TermTTTTGTTTGTTTGTAGCGATACAAACTTGGAGTTCGCTTGTAT
CGA to TGATACCGAGTAATGGAATCCATGCTTAAATCAGTAA
TTACTGATTTAAGCATGGATTCCATTACTCGGTAATACAAGCG558
AACTCCAAGTTTGTATCGCTACAAACAAACAAAAAGAAAAATA
AGAGCCTGCTATTTTAGAAAATCACAATTATGAAA
GTTTGTAGCGATACAAA559
TTTGTATCGCTACAAAC560
RetinoblastomaGCTCTTATTTTTCTTTTTGTTTGTTTGTAGCGATACAAACTTGG561
Arg455TermAGTTCGCTTGTATTACCGAGTAATGGAATCCATGCTTAAATCA
CGA to TGAGTAAGTTAAAAACAATATAAAAAAATTTCAGCCG
CGGCTGAAATTTTTTTATATTGTTTTTAACTTACTGATTTAAGC562
ATGGATTCCATTACTCGGTAATACAAGCGAACTCCAAGTTTGT
ATCGCTACAAACAAACAAAAAGAAAAATAAGAGC
TGTATTACCGAGTAATG563
CATTACTCGGTAATACA564
RetinoblastomaATCGAAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAA565
Arg552TermATGATAAAACATTTAGAACGATGTGAACATCGAATCATGGAAT
CGA to TGACCCTTGCATGGCTCTCAGTAAGTAGCTAAATAATTG
CAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGATTCCAT566
GATTCGATGTTCACATCGTTCTAAATGTTTTATCATTTCTCTTG
TCAAGTTGCCTTCTGCTTTGATAAAACTTTCGAT
ATTTAGAACGATGTGAA567
TTCACATCGTTCTAAAT568
RetinoblastomaAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATA569
Cys553TermAAACATTTAGAACGATGTGAACATCGAATCATGGAATCCCTTG
TGT to TGACATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAA
TTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGAT570
TCCATGATTCGATGTTCACATCGTTCTAAATGTTTTATCATTTC
TCTTGTCAAGTTGCCTTCTGCTTTGATAAAACTT
GAACGATGTGAACATCG571
CGATGTTCACATCGTTC572
RetinoblastomaAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATAA573
Glu554TermAACATTTAGAACGATGTGAACATCGAATCATGGAATCCCTTG
GAA to TAACATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAAA
TTTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGA574
TTCCATGATTCGATGTTCACATCGTTCTAAATGTTTTATCATTT
CTCTTGTCAAGTTGCCTTCTGCTTTGATAAAACT
AACGATGTGAACATCGA575
TCGATGTTCACATCGTT576
RetinoblastomaTACCTGGGAAAATTATGCTTACTAATGTGGTTTTAATTTCATC577
Ser567LeuATGTTTCATATAGGATTCACCTTTATTTGATCTTATTAAACAAT
TCA to TTACAAAGGACCGAGAAGGACCAACTGATCACCTTGA
TCAAGGTGATCAGTTGGTCCTTCTCGGTCCTTTGATTGTTTAA578
TAAGATCAAATAAAGGTGAATCCTATATGAAACATGATGAAAT
TAAAACCACATTAGTAAGCATAATTTTCCCAGGTA
ATAGGATTCACCTTTAT579
ATAAAGGTGAATCCTAT580
RetinoblastomaAATGTGGTTTTAATTTCATCATGTTTCATATAGGATTCACCTTT581
Gln575TermATTTGATCTTATTAAACAATCAAAGGACCGAGAAGGACCAACT
CAA to TAAGATCACCTTGAATCTGCTTGTCCTCTTAATCTTC
GAAGATTAAGAGGACAAGCAGATTCAAGGTGATCAGTTGGTC582
CTTCTCGGTCCTTTGATTGTTTAATAAGATCAAATAAAGGTGA
ATCCTATATGAAACATGATGAAATTAAAACCACATT
TTATTAAACAATCAAAG583
CTTTGATTGTTTAATAA584
RetinoblastomaATTTCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTAT585
Arg579TermTAAACAATCAAAGGACCGAGAAGGACCAACTGATCACCTTGA
CGA to TGAATCTGCTTGTCCTCTTAATCTTCCTCTCCAGAATA
TATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAAGGT586
GATCAGTTGGTCCTTCTCGGTCCTTTGATTGTTTAATAAGATC
AAATAAAGGTGAATCCTATATGAAACATGATGAAAT
CAAAGGACCGAGAAGGA587
TCCTTCTCGGTCCTTTG588
RetinoblastomaTCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTATTAA589
Glu58OTermACAATCAAAGGACCGAGAAGGACCAACTGATCACCTTGAATC
GAA to TAATGCTTGTCCTCTTAATCTTCCTCTCCAGAATAATC
GATTATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAA590
GGTGATCAGTTGGTCCTTCTCGGTCCTTTGATTGTTTAATAAG
ATCAAATAAAGGTGAATCCTATATGAAACATGATGA
AGGACCGAGAAGGACCA591
TGGTCCTTCTCGGTCCT592
RetinoblastomaAGAAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATG593
Ser634TermCAGAGACACAAGCAACCTCAGCCTTCCAGACCCAGAAGCCA
TCA to TGATTGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGG
CCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGGCT594
TCTGGGTCTGGAAGGCTGAGGTTGCTTGTGTCTCTGCATTTG
CAGTAGAATTTACACGCGTAGTTGAACCTTTTTTCT
AGCAACCTCAGCCTTCC595
GGAAGGCTGAGGTTGCT596
RenoblastomaAAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATGCA597
Ala635ProGAGACACAAGCAACCTCAGCCTTCCAGACCCAGAAGCCATT
GCC to CCCGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGGTT
AACCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGG598
CTTCTGGGTCTGGAAGGCTGAGGTTGCTTGTGTCTCTGCATT
TGCAGTAGAATTTACACGCGTAGTTGAACCTTTTTT
CAACCTCAGCCTTCCAG599
CTGGAAGGCTGAGGTTG600
RetinoblastomaACTACGCGTGTAAATTCTACTGCAAATGCAGAGACACAAGCA601
Gln639TermACCTCAGCCTTCCAGACCCAGAAGCCATTGAAATCTACCTCT
CAG to TAGCTTTCACTGTTTTATAAAAAAGGTTAGTAGATGATTA
TAATCATCTACTAACCTTTTTTATAAAACAGTGAAAGAGAGGT602
AGATTTCAATGGCTTCTGGGTCTGGAAGGCTGAGGTTGCTTG
TGTCTCTGCATTTGCAGTAGAATTTACACGCGTAGT
TCCAGACCCAGAAGCCA603
TGGCTTCTGGGTCTGGA604
RetinoblastomaTTGTAATTCAAAATGAACAGTAAAAATGACTAATTTTTCTTATT605
Leu657ProCCCACAGTGTATCGGCTAGCCTATCTCCGGCTAAATACACTT
CTA to CCATGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGA
TCTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAAGTGTA606
TTTAGCCGGAGATAGGCTAGCCGATACACTGTGGGAATAAG
AAAAATTAGTCATTTTTACTGTTCATTTTGAATTACAA
GTATCGGCTAGCCTATC607
GATAGGCTAGCCGATAC608
RetinoblastomaAATGAACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTA609
Arg661TrpTCGGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGCCT
CGG to TGGTCTGTCTGAGCACCCAGAATTAGAACATATCATCT
AGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGGCGTT610
CACAAAGTGTATTTAGCCGGAGATAGGCTAGCCGATACACTG
TGGGAATAAGAAAAATTAGTCATTTTTACTGTTCATT
CCTATCTCCGGCTAAAT611
ATTTAGCCGGAGATAGG612
RetinoblastomaAACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTATCG613
Leu662ProGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGCCTTCT
CTA to CCAGTCTGAGCACCCAGAATTAGAACATATCATCTGGAC
GTCCAGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGG614
CGTTCACAAAGTGTATTTAGCCGGAGATAGGCTAGCCGATAC
ACTGTGGGAATAAGAAAAATTAGTCATTTTTACTGTT
TCTCCGGCTAAATACAC615
GTGTATTTAGCCGGAGA616
RetinoblastomaTATCGGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGC617
Glu675TermCTTCTGTCTGAGCACCCAGAATTAGAACATATCATCTGGACC
GAA to TAACTTTTCCAGCACACCCTGCAGAATGAGTATGAACTCA
TGAGTTCATACTCATTCTGCAGGGTGTGCTGGAAAAGGGTCC618
AGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGGCGTT
CACAAAGTGTATTTAGCCGGAGATAGGCTAGCCGATA
AGCACCCAGAATTAGAA619
TTCTAATTCTGGGTGCT620
RetinoblastomaTTTGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGAACATA621
Gln685ProTCATCTGGACCCTTTTCCAGCACACCCTGCAGAATGAGTATG
CAG to CCGAACTCATGAGAGACAGGCATTTGGACCAAGTAAGAAA
TTTCTTACTTGGTCCAAATGCCTGTCTCTCATGAGTTCATACT622
CATTCTGCAGGGTGTGCTGGAAAAGGGTCCAGATGATATGTT
CTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAA
CCTTTTCCAGCACACCC623
GGGTGTGCTGGAAAAGG624
RetinoblastomaAAAACCATGTAATAAAATTCTGACTACTTTTACATCAATTTATT625
Cys706TyrTACTAGATTATGATGTGTTCCATGTATGGCATATGCAAAGTGA
TGT to TATAGAATATAGACCTTAAATTCAAAATCATTGTAAC
GTTACAATGATTTTGAATTTAAGGTCTATATTCTTCACTTTGCA626
TATGCCATACATGGAACACATCATAATCTAGTAAATAAATTGA
TGTAAAAGTAGTCAGAATTTTATTACATGGTTTT
TATGATGTGTTCCATGT627
ACATGGAACACATCATA628
RetinoblastomaTTCTGACTACTTTTACATCAATTTATTTACTAGATTATGATGTG629
Cys712ArgTTCCATGTATGGCATATGCAAAGTGAAGAATATAGACCTTAAA
TGC to CGCTTCAAAATCATTGTAACAGCATACAAGGATCTTC
GAAGATCCTTGTATGCTGTTACAATGATTTTGAATTTAAGGTC630
TATATTCTTCACTTTGCATATGCCATACATGGAACACATCATA
ATCTAGTAAATAAATTGATGTAAAAGTAGTCAGAA
ATGGCATATGCAAAGTG631
CACTTTGCATATGCCAT632
RetinoblastomaGTATGGCATATGCAAAGTGAAGAATATAGACCTTAAATTCAAA633
Tyr728TermATCATTGTAACAGCATACAAGGATCTTCCTCATGCTGTTCAG
TAC to TAAGAGGTAGGTAATTTTCCATAGTAAGTTTTTTTGATA
TATCAAAAAAACTTACTATGGAAAATTACCTACCTCCTGAACA634
GCATGAGGAAGATCCTTGTATGCTGTTACAATGATTTTGAATT
TAAGGTCTATATTCTTCACTTTGCATATGCCATAC
ACAGCATACAAGGATCT635
AGATCCTTGTATGCTGT636
RetinoblastomaTTTTTTTTTTTTTTTACTGTTCTTCCTCAGACATTCAAACGTGT637
Glu748TermTTTGATCAAAGAAGAGGAGTATGATTCTATTATAGTATTCTATA
GAG to TAGACTCGGTCTTCATGCAGAGACTGAAAACAAATA
TATTTGTTTTCAGTCTCTGCATGAAGACCGAGTTATAGAATAC638
TATAATAGAATCATACTCCTCTTCTTTGATCAAAACACGTTTGA
ATGTCTGAGGAAGAACAGTAAAAAAAAAAAAAAA
AAGAAGAGGAGTATGAT639
ATCATACTCCTCTTCTT640
RetinoblastomaGTTTTGATCAAAGAAGAGGAGTATGATTCTATTATAGTATTCT641
Gln762TermATAACTCGGTCTTCATGCAGAGACTGAAAACAAATATTTTGCA
CAG to TAGGTATGCTTCCACCAGGGTAGGTCAAAAGTATCCTT
AAGGATACTTTTGACCTACCCTGGTGGAAGCATACTGCAAAA642
TATTTGTTTTCAGTCTCTGCATGAAGACCGAGTTATAGAATAC
TATAATAGAATCATACTCCTCTTCTTTGATCAAAAC
TCTTCATGCAGAGACTG643
CAGTCTCTGCATGAAGA644
RetinoblastomaTAATCTACTTTTTTGTTTTTGCTCTAGCCCCCTACCTTGTCAC645
Arg787TermCAATACCTCACATTCCTCGAAGCCCTTACAAGTTTCCTAGTTC
CGA-TGAACCCTTACGGATTCCTGGAGGGAACATCTATATTT
AAATATAGATGTTCCCTCCAGGAATCCGTAAGGGTGAACTAG646
GAAACTTGTAAGGGCTTCGAGGAATGTGAGGTATTGGTGACA
AGGTAGGGGGCTAGAGCAAAAACAAAAAAGTAGATTA
ACATTCCTCGAAGCCCT647
AGGGCTTCGAGGAATGT648
RetinoblastomaCCTTACGGATTCCTGGAGGGAACATCTATATTTCACCCCTGA649
Ser816TermAGAGTCCATATAAAATTTCAGAAGGTCTGCCAACACCAACAA
TCA to TGAAAATGACTCCAAGATCAAGGTGTGTGTTTTCTCTTTA
TAAAGAGAAAACACACACCTTGATCTTGGAGTCATTTTTGTTG650
GTGTTGGCAGACCTTCTGAAATTTTATATGGACTCTTCAGGG
GTGAAATATAGATGTTCCCTCCAGGAATCCGTAAGG
TAAAATTTCAGAAGGTC651
GACCTTCTGAAATTTTA652
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BRCA1 and BRCA2
[0123] Breast cancer is the second major cause of cancer death in American women, with an estimated 44,190 lives lost (290 men and 43,900 women) in the US in 1997. While ovarian cancer accounts for fewer deaths than breast cancer, it still represents 4% of all female cancers. In 1994, two breast cancer susceptibility genes were identified: BRCA1 on chromosome 17 and BRCA2 on chromosome 13. When a woman carries a mutation in either BRCA1 or BRCA2, she is at increased risk of being diagnosed with breast or ovarian cancer at some point in her life.
[0124] Ford et al., Am. J. Hum. Genet. 62: 676-689 (1998) assessed the contribution of BRCA1 and BRCA2 to inherited breast cancer by linkage and mutation analysis in 237 families, each with at least 4 cases of breast cancer. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16%, suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority (76%) of families with both male and female breast cancer were due to BRCA2. The largest proportion (67%) of families due to other genes were families with 4 or 5 cases of female breast cancer only.
[0125] More than 75% of the reported mutations in the BRCA1 gene result in truncated proteins. Couch et al., Hum. Mutat. 8: 8-18, 1996. (1996) reported a total of 254 BRCA1 mutations, 132 (52%) of which were unique. A total of 221 (87%) of all mutations or 107 (81%) of the unique mutations are small deletions, insertions, nonsense point mutations, splice variants, and regulatory mutations that result in truncation or absence of the BRCA1 protein. A total of 11 disease-associated missense mutations (5 unique) and 21 variants (19 unique) as yet unclassified as missense mutations or polymorphisms had been detected. Thirty-five independent benign polymorphisms had been described. The most common mutations were 185delAG and 5382insC, which accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the mutations.
[0126] Most BRCA2 mutations are predicted to result in a truncated protein product The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are critical for BRCA2 function. Studies (Spain et al., Proc. Natl. Acad. Sci. 96:13920-13925 (1999)) suggest that such truncations eliminate or interfere with 2 nuclear localizaton signals that reside within the final 156 residues of BRCA2, suggesting that the vast majority of BRCA2 mutants are nonfunctional because they are not translocated into the nucleus.
[0127] The attached table discloses the correcting oligonucleotide base sequences for the BRACA1 and BRACA2 oligonucleotides of the invention.
15TABLE 14
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BRCA1 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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Breast CancerCTGCGCTCAGGAGGCCTTCACCCTCTGCTCTGGGTAAAGTT653
Met-1-IleCATTGGAACAGAAAGAAATGGATTTATCTGCTCTTCGCGTTG
ATG to ATTAAGAAGTACAAAATGTCATTAATGCTATGCAGAAAATC
GATTTTCTGCATAGCATTAATGACATTTTGTACTTCTTCAACG654
CGAAGAGCAGATAAATCCATTTCTTTCTGTTCCAATGAACTTT
ACCCAGAGCAGAGGGTGAAGGCCTCCTGAGCGCAG
AAAGAAATGGATTTATC655
GATAAATCCATTTCTTT656
Breast CancerCTGGGTAAAGTTCATTGGAACAGAAAGAAATGGATTTATCTG657
Val-11-AlaCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAATGCTATGCA
GTA to GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGAT
ATCAACTCCAGACAGATGGGACACTCTAAGATTTTCTGCATA658
GCATTAATGACATTTTGTACTTCTTCAACGCGAAGAGCAGATA
AATCCATTTCTTTCTGTTCCAATGAACTTTACCCAG
TGAAGAAGTACAAAATG659
CATTTTGTACTTCTTCA660
Breast CancerATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCA661
Ile-21-ValTTAATGCTATGCAGAAAATCTTAGAGTGTCCCATCTGTCTGG
ATC to GTCAGTTGATCAAGGAACCTGTCTCCACAAAGTGTGACC
GGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCCAGAC662
AGATGGGACACTCTAAGATTTTCTGCATAGCATTAATGACATT
TTGTACTTCTTCAACGCGAAGAGCAGATAAATCCAT
TGCAGAAAATCTTAGAG663
CTCTAAGATTTTCTGCA664
Breast CancerATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAA665
Leu-22-SerTGCTATGCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTT
TTA to TCAGATCAAGGAACCTGTCTCCACAAAGTGTGACCACAT
ATGTGGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCC666
AGACAGATGGGACACTCTAAGATTTTCTGCATAGCATTAATG
ACATTTTGTACTTCTTCAACGCGAAGAGCAGATAAAT
GAAAATCTTAGAGTGTC667
GACACTCTAAGATTTTC668
Breast CancerAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGG669
Cys-39-TyrAACCTGTCTCCACAAAGTGTGACCACATATTTTGCAAATTTTG
TGT to TATCATGCTGAAACTTCTCAACCAGAAGAAAGGGCCTTC
GAAGGCCCTTTCTTCTGGTTGAGAAGTTTCAGCATGCAAAAT670
TTGCAAAATATGTGGTCACACTTTGTGGAGACAGGTTCCTTG
ATCAACTCCAGACAGATGGGACACTCTAAGATTTTCT
CACAAAGTGTGACCACA671
TGTGGTCACACTTTGTG672
Breast CancerCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGA673
Cys-61-GlyAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGATATAAC
TGT to GGTCAAAAGGAGCCTACAAGAAAGTACGAGATTTAGTC
GACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGGTTATATC674
ATTCTTACATAAAGGACACTGTGAAGGCCCTTTCTTCTGGTT
GAGAAGTTTCAGCATGCAAAATTTGCAAAATATGTG
CTTCACAGTGTCCTTTA675
TAAAGGACACTGTGAAG676
Breast CancerTTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGG677
Leu-63-StopGCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAAGG
TTA to TAAAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGT
ACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGG678
TTATATCATTCTTACATAAAGGACACTGTGAAGGCCCTTTCTT
CTGGTTGAGAAGTTTCAGCATGCAAAATTTGCAAA
GTGTCCTTTATGTAAGA679
TCTTACATAAAGGACAC680
Breast CancerTGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGG681
Cys-64-ArgCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAAGGA
TGT to CGTGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTG
Breast CancerCAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTT682
Cys-64-GlyGGTTATATCATTCTTACATAAAGGACACTGTGAAGGCCCTTTC
TGT to GGTTTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGCA
GTCCTTTATGTAAGAAT683
ATTCTTACATAAAGGAC684
Breast CancerGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGGC685
Cys-64-TyrCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAAGGAG
TGT to TATCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGA
TCAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTT686
TGGTTATATCATTCTTACATAAAGGACACTGTGAAGGCCCTTT
CTTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGC
TCCTTTATGTAAGAATG687
CATTCTTACATAAAGGA688
Breast CancerCAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGAT689
Gln-74-StopATAACCAAAAGGAGCCTACAAGAAAGTACGAGATTTAGTCAA
CAA to TAACTTGTTGAAGAGCTATTGAAAATCATTTGTGCTTTTC
GAAAAGCACAAATGATTTTCAATAGCTCTTCAACAAGTTGACT690
AAATCTCGTACTTTCTTGTAGGCTCCTTTTGGTTATATCATTCT
TACATAAAGGACACTGTGAAGGCCCTTTCTTCTG
GGAGCCTACAAGAAAGT691
ACTTTCTTGTAGGCTCC692
Breast CancerAGCTATTGAAAATCATTTGTGCTTTTCAGCTTGACACAGGTTT693
Tyr-105-CysGGAGTATGCAAACAGCTATAATTTTGCAAAAAAGGAAAATAAC
TAT to TGTTCTCCTGAACATCTAAAAGATGAAGTTTCTATCAT
ATGATAGAAACTTCATCTTTTAGATGTTCAGGAGAGTTATTTT694
CCTTTTTTGCAAAATTATAGCTGTTTGCATACTCCAAACCTGT
GTCAAGCTGAAAAGCACAAATGATTTTCAATAGCT
AAACAGCTATAATTTTG695
CAAAATTATAGCTGTTT696
Breast CancerCTACAGAGTGAACCCGAAAATCCTTCCTTGCAGGAAACCAGT697
Asn-158-TyrCTCAGTGTCCAACTCTCTAACCTTGGAACTGTGAGAACTCTG
AAC to TACAGGACAAAGCAGCGGATACAACCTCAAAAGACGTCTG
CAGACGTCTTTTGAGGTTGTATCCGCTGCTTTGTCCTCAGAG698
TTCTCACAGTTCCAAGGTTAGAGAGTTGGACACTGAGACTGG
TTTCCTGCAAGGAAGGATTTTCGGGTTCACTCTGTAG
AACTCTCTAACCTTGGA699
TCCAAGGTTAGAGAGTT700
Breast CancerGAAACCAGTCTCAGTGTCCAACTCTCTAACCTTGGAACTGTG701
Gln-169-StopAGAACTCTGAGGACAAAGCAGCGGATACAACCTCAAAAGAC
CAG to TAGGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAG
CTTCAGAAGAATCAGATCCCAATTCAATGTAGACAGACGTCTT702
TTGAGGTTGTATCCGCTGCTTTGTCCTCAGAGTTCTCACAGT
TCCAAGGTTAGAGAGTTGGACACTGAGACTGGTTTC
GGACAAAGCAGCGGATA703
TATCCGCTGCTTTGTCC704
Breast CancerCTCCCAGCACAGAAAAAAAGGTAGATCTGAATGCTGATCCCC705
Trp-353-StopTGTGTGAGAGAAAAGAATGGAATAAGCAGAAACTGCCATGCT
TGG to TAGCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGAT
ATCCAAGGAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT706
GGCAGTTTCTGCTTATTCCATTCTTTTCTCTCACACAGGGGAT
CAGCATTCAGATCTACCTTTTTTTCTGTGCTGGGAG
AAAAGAATGGAATAAGC707
GCTTATTCCATTCTTTT708
Breast CancerATGCTCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGAT709
Ile-379-MetAACACTAAATAGCAGCATTCAGAAAGTTAATGAGTGGTTTTCC
ATT to ATGAGAAGTGATGAACTGTTAGGTTCTGATGACTCACAT
ATGTGAGTCATCAGAACCTAACAGTTCATCACTTCTGGAAAAC710
CACTCATTAACTTTCTGAATGCTGCTATTTAGTGTTATCCAAG
GAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT
AGCAGCATTCAGAAAGT711
ACTTTCTGAATGCTGCT712
Breast CancerGGGAGTCTGAATCAAATGCCAAAGTAGCTGATGTATTGGACG713
Glu-421-GlyTTCTAAATGAGGTAGATGAATATTCTGGTTCTTCAGAGAAAAT
GAA to GGAAGACTTACTGGCCAGTGATCCTCATGAGGCTTTAAT
ATTAAAGCCTCATGAGGATCACTGGCCAGTAAGTCTATTTTCT714
CTGAAGAACCAGAATATTCATCTACCTCATTTAGAACGTCCAA
TACATCAGCTACTTTGGCATTTGATTCAGACTCCC
GGTAGATGAATATTCTG715
CAGAATATTCATCTACC716
Breast CancerATATGTAAAAGTGAAAGAGTTCACTCCAAATCAGTAGAGAGTA717
Phe-461-LeuATATTGAAGACAAAATATTTGGGAAAACCTATCGGAAGAAGG
TTT to CTTCAAGCCTCCCCAACTTAAGCCATGTAACTGAAAATC
GATTTTCAGTTACATGGCTTAAGTTGGGGAGGCTTGCCTTCT718
TCCGATAGGTTTTCCCAAATATTTTGTCTTCAATATTACTCTCT
ACTGATTTGGAGTGAACTCTTTCACTTTTACATAT
ACAAAATATTTGGGAAA719
TTTCCCAAATATTTTGT720
Breast CancerGAAAGAGTTCACTCCAAATCAGTAGAGAGTAATATTGAAGAC721
Tyr-465-LeuAAAATATTTGGGAAAACCTATCGGAAGAAGGCAAGCCTCCCC
TAT to GATAACTTAAGCCATGTAACTGAAAATCTAATTATAGGAG
CTCCTATAATTAGATTTTCAGTTACATGGCTTAAGTTGGGGAG722
GCTTGCCTTCTTCCGATAGGTTTTCCCAAATATTTTGTCTTCA
ATATTACTCTCTACTGATTTGGAGTGAACTCTTTC
GGAAAACCTATCGGAAG723
CTTCCGATAGGTTTTCC724
Breast CancerACCTATCGGAAGAAGGCAAGCCTCCCCAACTTAAGCCATGTA725
Gly-484-StopACTGAAAATCTAATTATAGGAGCATTTGTTACTGAGCCACAGA
GGA to TGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGC
GCTTTAATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTGG726
CTCAGTAACAAATGCTCCTATAATTAGATTTTCAGTTACATGG
CTTAAGTTGGGGAGGCTTGCCTTCTTCCGATAGGT
TAATTATAGGAGCATTT727
AAATGCTCCTATAATTA728
Breast CancerTTACTGAGCCACAGATAATACAAGAGCGTCCCCTCACAAATA729
Arg-507-IleAATTAAAGCGTAAAAGGAGACCTACATCAGGCCTTCATCCTG
AGA to ATAAGGATTTTATCAAGAAAGCAGATTTGGCAGTTCMAA
TTTTGAACTGCCAAATCTGCTTTCTTGATAAAATCCTCAGGAT730
GAAGGCCTGATGTAGGTCTCCTTTTACGCTTTAATTTATTTGT
GAGGGGACGCTCTTGTATTATCTGTGGCTCAGTAA
TAAAAGGAGACCTACAT731
ATGTAGGTCTCCTTTTA732
Breast CancerCACAGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGC733
Ser-510-StopGTAAAAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTA
TCA to TGATCAAGAAAGCAGATTTGGCAGTTCAAAAGACTCCTGA
TCAGGAGTCTTTTGAACTGCCAAATCTGCTTTCTTGATAAAAT734
CCTCAGGATGAAGGCCTGATGTAGGTCTCCTTTTACGCTTTA
ATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTG
ACCTACATCAGGCCTTC735
GAAGGCCTGATGTAGGT736
Breast CancerAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG737
Gln-526-StopAAAGCAGATTTGGCAGTTCAAAAGACTCCTGAAATGATAAATC
CAA to TAAAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA
TCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT738
CATTTCAGGAGTCTTTTGAACTGCCAAATCTGCTTTCTTGATA
AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT
TGGCAGTTCAAAAGACT739
AGTCTTTTGAACTGCCA740
Breast CancerAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG741
Gln-541-StopAAAGCAGATTTGGCAGTTCAAAAGACTCCTGAAATGATAAATC
CAG to TAGAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA
TCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT742
CATTTCAGGAGTCTTTTGAACTGCCAAATCTGCTTTCTTGATA
AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT
AAACGGAGCAGAATGGT743
ACCATTCTGCTCCGTTT744
Breast CancerTAAATCAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA745
Gly-552-ValTGAATATTACTAATAGTGGTCATGAGAATAAAACAAAAGGTGA
GGT to GTTTTCTATTCAGAATGAGAAAAATCCTAACCCAATAGA
TCTATTGGGTTAGGATTTTTCTCATTCTGAATAGAATCACCTTT746
TGTTTTATTCTCATGACCACTATTAGTAATATTCATCACTTGAC
CATTCTGCTCCGTTTGGTTAGTTCCCTGATTTA
TAATAGTGGTCATGAGA747
TCTCATGACCACTATTA748
Breast CancerGGTCAAGTGATGAATATTACTAATAGTGGTCATGAGAATAAAA749
Gln-563-StopCAAAAGGTGATTCTATTCAGAATGAGAAAAATCCTAACCCAAT
CAG to TAGAGAATCACTCGAAAAAGAATCTGCTTTCAAAACGA
TCGTTTTGAAAGCAGATTCTTTTTCGAGTGATTCTATTGGGTT750
AGGATTTTTCTCATTCTGAATAGAATCACCTTTTGTTTTATTCT
CATGACCACTATTAGTAATATTCATCACTTGACC
ATTCTATTCAGAATGAG751
CTCATTCTGAATAGAAT752
Ovarian CancerATAAGCAGCAGTATAAGCAATATGGAACTCGAATTAAATATCC753
Lys-607-StopACAATTCAAAAGCACCTAAAAAGAATAGGCTGAGGAGGAAGT
AAA to TAACTTCTACCAGGCATATTCATGCGCTTGAACTAGTAG
CTACTAGTTCAAGCGCATGAATATGCCTGGTAGAAGACTTCC754
TCCTCAGCCTATTCTTTTTAGGTGCTTTTGAATTGTGGATATT
TAATTCGAGTTCCATATTGCTTATACTGCTGCTTAT
AAGCACCTAAAAAGAAT755
ATTCTTTTTAGGTGCTT756
Breast CancerATATTCATGCGCTTGAACTAGTAGTCAGTAGAAATCTAAGCCC757
Leu-639-StopACCTAATTGTACTGAATTGCAAATTGATAGTTGTTCTAGCAGT
TTG to TAGGAAGAGATAAAGAAAAAAAAGTACAACCAAATGCC
GGCATTTGGTTGTACTTTTTTTTCTTTATCTCTTCACTGCTAGA758
ACAACTATCAATTTGCAATTCAGTACAATTAGGTGGGCTTAGA
TTTCTACTGACTACTAGTTCAAGCGCATGAATAT
TACTGAATTGCAAATTG759
CAATTTGCAATTCAGTA760
Breast CancerGAACCTGCAACTGGAGCCAAGAAGAGTAACAAGCCAAATGAA761
Asp-693-AsnCAGACAAGTAAAAGACATGACAGCGATACTTTCCCAGAGCTG
GAC to AACAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTT
AACACTTAGTAAAAGAACCAGGTGCATTTGTTAACTTCAGCTC762
TGGGAAAGTATCGCTGTCATGTCTTTTACTTGTCTGTTCATTT
GGCTTGTTACTCTTCTTGGCTCCAGTTGCAGGTTC
AAAGACATGACAGCGAT763
ATCGCTGTCATGTCTTT764
Ovarian CancerCTGAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTTCAA765
Glu-720-StopATACCAGTGAACTTAAAGAATTTGTCAATCCTAGCCTTCCAAG
GAA to TAAAGAAGAAAAAGAAGAGAAACTAGAAACAGTTAAAG
CTTTAACTGTTTCTAGTTTCTCTTCTTTTTCTTCTCTTGGAAGG766
CTAGGATTGACAAATTCTTTAAGTTCACTGGTATTTGAACACT
TAGTAAAAGAACCAGGTGCATTTGTTAACTTCAG
AACTTAAAGAATTTGTC767
GACAAATTCTTTAAGTT768
Breast CancerCTAGAAACAGTTAAAGTGTCTAATAATGCTGAAGACCCCAAA769
Glu-755-StopGATCTCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGA
GAA to TAATCTGTAGAGAGTAGCAGTATTTCATTGGTACCTGGTA
TACCAGGTACCAATGAAATACTGCTACTCTCTACAGATCTTTC770
AGTTTGCAAAACCCTTTCTCCACTTAACATGAGATCTTTGGGG
TCTTCAGCATTATTAGACACTTTAACTGTTTCTAG
TAAGTGGAGAAAGGGTT771
AACCCTTTCTCCACTTA772
Breast CancerTCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTG773
Ser-770-StopTAGAGAGTAGCAGTATTTCATTGGTACCTGGTACTGATTATG
TCA to TAAGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCAC
GTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTGCCATAA774
TCAGTACCAGGTACCAATGAAATACTGCTACTCTCTACAGAT
CTTTCAGTTTGCAAAACCCTTTCTCCACTTAACATGA
CAGTATTTCATTGGTAC775
GTACCAATGAAATACTG776
Breast CancerTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTGTAGAGA777
Val-772-AlaGTAGCAGTATTTCATTGGTACCTGGTACTGATTATGGCACTC
GTA to GCAAGGAAAGTATCTCGTTACTGGAAGTTAGCACTCTAGG
CCTAGAGTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTG778
CCATAATCAGTACCAGGTACCAATGAAATACTGCTACTCTCTA
CAGATCTTTCAGTTTGCAAAACCCTTTCTCCACTTA
TTCATTGGTACCTGGTA779
TACCAGGTACCAATGAA780
Breast CancerACTGAAAGATCTGTAGAGAGTAGCAGTATTTCATTGGTACCT781
Gln-780-StopGGTACTGATTATGGCACTCAGGAAAGTATCTCGTTACTGGAA
CAG to TAGGTTAGCACTCTAGGGAAGGCAAAAACAGAACCAAATA
TATTTGGTTCTGTTTTTGCCTTCCCTAGAGTGCTAACTTCCAG782
TAACGAGATACTTTCCTGAGTGCCATAATCAGTACCAGGTAC
CAATGAAATACTGCTACTCTCTACAGATCTTTCAGT
ATGGCACTCAGGAAAGT783
ACTTTCCTGAGTGCCAT784
Breast CancerTATGGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCACT785
Glu-797-StopCTAGGGAAGGCAAAAACAGAACCAAATAAATGTGTGAGTCAG
GAA to TAATGTGCAGCATTTGAAAACCCCAAGGGACTAATTCATG
CATGAATTAGTCCCTTGGGGTTTTCAAATGCTGCACACTGAC786
TCACACATTTATTTGGTTCTGTTTTTGCCTTCCCTAGAGTGCT
AACTTCCAGTAACGAGATACTTTCCTGAGTGCCATA
CAAAAACAGAACCAAAT787
ATTTGGTTCTGTTTTTG788
Breast CancerAAATGTGTGAGTCAGTGTGCAGCATTTGAAAACCCCAAGGGA789
Lys-820-GluCTAATTCATGGTTGTTCCAAAGATAATAGAAATGACACAGAAG
AAA to GAAGCTTTAAGTATCCATTGGGACATGAAGTTAACCACA
TGTGGTTAACTTCATGTCCCAATGGATACTTAAAGCCTTCTGT790
GTCATTTCTATTATCTTTGGAACAACCATGAATTAGTCCCTTG
GGGTTTTCAAATGCTGCACACTGACTCACACATTT
GTTGTTCCAAAGATAAT791
ATTATCTTTGGAACAAC792
Breast CancerCAGCATTTGAAAACCCCAAGGGACTAATTCATGGTTGTTCCA793
Thr-826-LysAAGATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTGG
ACA to AAAGACATGAAGTTAACCACAGTCGGGAAACAAGCATAGA
TCTATGCTTGTTTCCCGACTGTGGTTAACTTCATGTCCCAATG794
GATACTTAAAGCCTTCTGTGTCATTTCTATTATCTTTGGAACA
ACCATGAATTAGTCCCTTGGGGTTTTCAAATGCTG
AAATGACACAGAAGGCT795
AGCCTTCTGTGTCATTT796
Breast CancerGATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTGGGA797
Arg-841-TrpCATGAAGTTAACCACAGTCGGGAAACAAGCATAGAAATGGAA
CGG to TGGGAAAGTGAACTTGATGCTCAGTATTTGCAGAATACAT
ATGTATTCTGCAAATACTGAGCATCAAGTTCACTTTCTTCCAT798
TTCTATGCTTGTTTCCCGACTGTGGTTAACTTCATGTCCCAAT
GGATACTTAAAGCCTTCTGTGTCATTTCTATTATC
ACCACAGTCGGGAAACA799
TGTTTCCCGACTGTGGT800
Breast CancerAACTTGATGCTCAGTATTTGCAGAATACATTCAAGGTTTCAAA801
Pro-871-LeuGCGCCAGTCATTTGCTCCGTTTTCAAATCCAGGAAATGCAGA
CCG to CTGAGAGGAATGTGCAACATTCTCTGCCCACTCTGGGTC
GACCCAGAGTGGGCAGAGAATGTTGCACATTCCTCTTCTGCA802
TTTCCTGGATTTGAAAACGGAGCAAATGACTGGCGCTTTGAA
ACCTTGAATGTATTCTGCAAATACTGAGCATCAAGTT
ATTTGCTCCGTTTTCAA803
TTGAAAACGGAGCAAAT804
Breast CancerTTTCAAATCCAGGAAATGCAGAAGAGGAATGTGCAACATTCT805
Leu-892-SerCTGCCCACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCA
TTA to TCACTTTTGAATGTGAACAAAAGGAAGAAAATCAAGGAAA
TTTCCTTGATTTTCTTCCTTTTGTTCACATTCAAAAGTGACTTT806
TGGACTTTGTTTCTTTAAGGACCCAGAGTGGGCAGAGAATGT
TGCACATTCCTCTTCTGCATTTCCTGGATTTGAAA
TGGGTCCTTAAAGAAAC807
GTTTCTTTAAGGACCCA808
Breast CancerCACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCACTTTTG809
Glu-908-StopAATGTGAACAAAAGGAAGAAAATCAAGGAAAGAATGAGTCTA
GAA to TAAATATCAAGCCTGTACAGACAGTTAATATCACTGCAG
CTGCAGTGATATTAACTGTCTGTACAGGCTTGATATTAGACTC810
ATTCTTTCCTTGATTTTCTTCCTTTTGTTCACATTCAAAAGTGA
CTTTTGGACTTTGTTTCTTTAAGGACCCAGAGTG
AAAAGGAAGAAAATCAA811
TTGATTTTCTTCCTTTT812
Breast CancerATAATGCCAAATGTAGTATCAAAGGAGGCTCTAGGTTTTGTCT813
Gly-960-AspATCATCTCAGTTCAGAGGCAACGAAACTGGACTCATTACTCC
GGC to GACAAATAAACATGGACTTTTACAAAACCCATATCGTAT
ATACGATATGGGTTTTGTAAAAGTCCATGTTTATTTGGAGTAA814
TGAGTCCAGTTTCGTTGCCTCTGAACTGAGATGATAGACAAA
ACCTAGAGCCTCCTTTGATACTACATTTGGCATTAT
GTTCAGAGGCAACGAAA815
TTTCGTTGCCTCTGAAC816
Breast CancerATTTGTTAAAACTAAATGTAAGAAAAATCTGCTAGAGGAAAAC817
Met-1008-IleTTTGAGGAACATTCAATGTCACCTGAAAGAGAAATGGGAAAT
ATG to ATAGAGAACATTCCAAGTACAGTGAGCACAATTAGCCGT
ACGGCTAATTGTGCTCACTGTACTTGGAATGTTCTCATTTCCC818
ATTTCTCTTTCAGGTGACATTGAATGTTCCTCAAAGTTTTCCT
CTAGCAGATTTTTCTTACATTTAGTTTTAACAAAT
CATTCAATGTCACCTGA819
TCAGGTGACATTGAATG820
Breast CancerACTTTGAGGAACATTCAATGTCACCTGAAAGAGAAATGGGAA821
Thr-1025-IleATGAGAACATTCCAAGTACAGTGAGCACAATTAGCCGTAATA
ACA to ATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTCAAG
CTTGAGCTGGCTTCTTTAAAAACATTTTCTCTAATGTTATTACG822
GCTAATTGTGCTCACTGTACTTGGAATGTTCTCATTTCCCATT
TCTCTTTCAGGTGACATTGAATGTTCCTCAAAGT
TCCAAGTACAGTGAGCA823
TGCTCACTGTACTTGGA824
Breast CancerACATTCCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAG825
Glu-1038-GlyAGAAAATGTTTTTAAAGAAGCCAGCTCAAGCAATATTAATGAA
GAA to GGAGTAGGTTCCAGTACTAATGAAGTGGGCTCCAGTAT
ATACTGGAGCCCACTTCATTAGTACTGGAACCTACTTCATTAA826
TATTGCTTGAGCTGGCTTCTTTAAAAACATTTTCTCTAATGTTA
TTACGGCTAATTGTGCTCACTGTACTTGGAATGT
TTTTAAAGAAGCCAGCT827
AGCTGGCTTCTTTAAAA828
Breast CancerCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAGAGAAA829
Ser-1040-AsnATGTTTTTAAAGAAGCCAGCTCAAGCAATATTAATGAAGTAGG
AGC to AACTTCCAGTACTAATGAAGTGGGCTCCAGTATTAATGA
TCATTAATACTGGAGCCCACTTCATTAGTACTGGAACCTACTT830
CATTAATATTGCTTGAGCTGGCTTCTTTAAAAACATTTTCTCTA
ATGTTATTACGGCTAATTGTGCTCACTGTACTTG
AGAAGCCAGCTCAAGCA831
TGCTTGAGCTGGCTTCT832
Breast CancerGCCGTAATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTC833
Val-1047-AlaAAGCAATATTAATGAAGTAGGTTCCAGTACTAATGAAGTGGG
GTA to GCACTCCAGTATTAATGAAATAGGTTCCAGTGATGAAAA
TTTTCATCACTGGAACCTATTTCATTAATACTGGAGCCCACTT834
CATTAGTACTGGAACCTACTTCATTAATATTGCTTGAGCTGGC
TTCTTTAAAAACATTTTCTCTAATGTTATTACGGC
TAATGAAGTAGGTTCCA835
TGGAACCTACTTCATTA836
Breast CancerAAATAGGTTCCAGTGATGAAAACATTCAAGCAGAACTAGGTA837
Leu-1080-StopGAAACAGAGGGCCAAAATTGAATGCTATGCTTAGATTAGGGG
TTG to TAGTTTTGCAACCTGAGGTCTATAAACAAAGTCTTCCTGG
CCAGGAAGACTTTGTTTATAGACCTCAGGTTGCAAAACCCCT838
AATCTAAGCATAGCATTCAATTTTGGCCCTCTGTTTCTACCTA
GTTCTGCTTGAATGTTTTCATCACTGGAACCTATTT
GCCAAAATTGAATGCTA839
TAGCATTCAATTTTGGC840
Breast CancerAAAACATTCAAGCAGAACTAGGTAGAAACAGAGGGCCAAAAT841
Leu-1086-StopTGAATGCTATGCTTAGATTAGGGGTTTTGCAACCTGAGGTCT
TTA to TGAATAAACAAAGTCTTCCTGGAAGTAATTGTAAGCATCC
GGATGCTTACAATTACTTCCAGGAAGACTTTGTTTATAGACCT842
CAGGTTGCAAAACCCCTAATCTAAGCATAGCATTCAATTTTG
GCCCTCTGTTTCTACCTAGTTCTGCTTGAATGTTTT
GCTTAGATTAGGGGTTT843
AAACCCCTAATCTAAGC844
Breast CancerAGCAAGAATATGAAGAAGTAGTTCAGACTGTTAATACAGATTT845
Ser-1130-StopCTCTCCATATCTGATTTCAGATAACTTAGAACAGCCTATGGGA
TCA to TGAAGTAGTCATGCATCTCAGGTTTGTTCTGAGACACC
GGTGTCTCAGAACAAACCTGAGATGCATGACTACTTCCCATA846
GGCTGTTCTAAGTTATCTGAAATCAGATATGGAGAGAAATCT
GTATTAACAGTCTGAACTACTTCTTCATATTCTTGCT
TCTGATTTCAGATAACT847
AGTTATCTGAAATCAGA848
Breast CancerCTAGTTTTGCTGAAAATGACATTAAGGAAAGTTCTGCTGTTTT849
Lys-1183-ArgTAGCAAAAGCGTCCAGAAAGGAGAGCTTAGCAGGAGTCCTA
AAA to AGAGCCCTTTCACCCATACACATTTGGCTCAGGGTTACCG
CGGTAACCCTGAGCCAAATGTGTATGGGTGAAAGGGCTAGG850
ACTCCTGCTAAGCTCTCCTTTCTGGACGCTTTTGCTAAAAACA
GCAGAACTTTCCTTAATGTCATTTTCAGCAAAACTAG
CGTCCAGAAAGGAGAGC851
GCTCTCCTTTCTGGACG852
Breast CancerAGCGTCCAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTT853
Gln-1200-StopCACCCATACACATTTGGCTCAGGGTTACCGAAGAGGGGCCA
GAG to TAGAGAAATTAGAGTCCTCAGAAGAGAACTTATCTAGTGAGG
CCTCACTAGATAAGTTCTCTTCTGAGGACTCTAATTTCTTGGC854
CCCTCTTCGGTAACCCTGAGCCAAATGTGTATGGGTGAAAGG
GCTAGGACTCCTGCTAAGCTCTCCTTTCTGGACGCT
ATTTGGCTCAGGGTTAC855
GTAACCCTGAGCCAAAT856
Breast CancerAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTTCACCCATACA857
Arg-1203-StopCATTTGGCTCAGGGTTACCGAAGAGGGGCCAAGAAATTAGA
CGA to TGAGTCCTCAGAAGAGAACTTATCTAGTGAGGATGAAGAGC
GCTCTTCATCCTCACTAGATAAGTTCTCTTCTGAGGACTCTAA858
TTTCTTGGCCCCTCTTCGGTAACCCTGAGCCAAATGTGTATG
GGTGAAAGGGCTAGGACTCCTGCTAAGCTCTCCTTT
AGGGTTACCGAAGAGGG859
CCCTCTTCGGTAACCCT860
Breast CancerACCCATACACATTTGGCTCAGGGTTACCGAAGAGGGGCCAA861
Glu-1214-StopGAAATTAGAGTCCTCAGAAGAGAACTTATCTAGTGAGGATGA
GAG to TAGAGAGCTTCCCTGCTTCCAACACTTGTTATTTGGTAAAG
CTTTACCAAATAACAAGTGTTGGAAGCAGGGAAGCTCTTCAT862
CCTCACTAGATAAGTTCTCTTCTGAGGACTCTAATTTCTTGGC
CCCTCTTCGGTAACCCTGAGCCAAATGTGTATGGGT
CCTCAGAAGAGAACTTA863
TAAGTTCTCTTCTGAGG864
Breast CancerTCAGGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAG865
Glu-1219-AspAAGAGAACTTATCTAGTGAGGATGAAGAGCTTCCCTGCTTCC
GAG to GACAACACTTGTTATTTGGTAAAGTAAACAATATACCTTCT
AGAAGGTATATTGTTTACTTTACCAAATAACAAGTGTTGGAAG866
CAGGGAAGCTCTTCATCCTCACTAGATAAGTTCTCTTCTGAG
GACTCTAATTTCTTGGCCCCTCTTCGGTAACCCTGA
TCTAGTGAGGATGAAGA867
TCTTCATCCTCACTAGA868
Breast CancerGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAGAAGA869
Glu-1221-StopGAACTTATCTAGTGAGGATGAAGAGCTTCCCTGCTTCCAACA
GAA to TAACTTGTTATTTGGTAAAGTAAACAATATACCTTCTCAGT
ACTGAGAAGGTATATTGTTTACTTTACCAAATAACAAGTGTTG
GAAGCAGGGAAGCTCTTCATCCTCACTAGATAAGTTCTCTTC
TGAGGACTCTAATTTCTTGGCCCCTCTTCGGTAACC
GTGAGGATGAAGAGCTT871
AAGCTCTTCATCCTCAC872
Breast CancerTTATTTGGTAAAGTAAACAATATACCTTCTCAGTCTACTAGGC873
Glu-1250-StopATAGCACCGTTGCTACCGAGTGTCTGTCTAAGAACACAGAGG
GAG to TAGAGAATTTATTATCATTGAAGAATAGCTTAAATGACT
AGTCATTTAAGCTATTCTTCAATGATAATAAATTCTCCTCTGTG874
TTCTTAGACAGACACTCGGTAGCAACGGTGCTATGCCTAGTA
GACTGAGAAGGTATATTGTTTACTTTACCAAATAA
TTGCTACCGAGTGTCTG875
CAGACACTCGGTAGCAA876
Breast CancerCTAGGCATAGCACCGTTGCTACCGAGTGTCTGTCTAAGAACA877
Ser-1262-StopCAGAGGAGAATTTATTATCATTGAAGAATAGCTTAAATGACTG
TCA to TAACAGTAACCAGGTAATATTGGCAAAGGCATCTCAGGA
TCCTGAGATGCCTTTGCCAATATTACCTGGTTACTGCAGTCAT878
TTAAGCTATTCTTCAATGATAATAAATTCTCCTCTGTGTTCTTA
GACAGACACTCGGTAGCAACGGTGCTATGCCTAG
TTTATTATCATTGAAGA879
TCTTCAATGATAATAAA880
Breast CancerTTATCATTGAAGAATAGCTTAAATGACTGCAGTAACCAGGTAA881
Gln-1281-StopTATTGGCAAAGGCATCTCAGGAACATCACCTTAGTGAGGAAA
CAG to TAGCAAAATGTTCTGCTAGCTTGTTTTCTTCACAGTGCA
TGCACTGTGAAGAAAACAAGCTAGCAGAACATTTTGTTTCCTC882
ACTAAGGTGATGTTCCTGAGATGCCTTTGCCAATATTACCTG
GTTACTGCAGTCATTTAAGCTATTCTTCAATGATAA
AGGCATCTCAGGAACAT883
ATGTTCCTGAGATGCCT884
Breast CancerGCTAGCTTGTTTTCTTCACAGTGCAGTGAATTGGAAGACTTG885
Gln-1313-StopACTGCAAATACAAACACCCAGGATCCTTTCTTGATTGGTTCTT
CAG-to-TAGCCAAACAAATGAGGCATCAGTCTGAAAGCCAGGGAG
CTCCCTGGCTTTCAGACTGATGCCTCATTTGTTTGGAAGAAC886
CAATCAAGAAAGGATCCTGGGTGTTTGTATTTGCAGTCAAGT
CTTCCAATTCACTGCACTGTGAAGAAAACAAGCTAGC
CAAACACCCAGGATCCT887
AGGATCCTGGGTGTTTG888
Breast CancerTCACAGTGCAGTGAATTGGAAGACTTGACTGCAAATACAAAC889
Ile-1318-ValACCCAGGATATCCTTTCTTGATTGGTTCTTCCAAACAAATGAGG
ATT to GTTCATCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACA
TGTCACTCAGACCAACTCCCTGGCTTTCAGACTGATGCCTCA890
TTTGTTTGGAAGAACCAATCAAGAAAGGATCCTGGGTGTTTG
TATTTGCAGTCAAGTCTTCCAATTCACTGCACTGTGA
CTTTCTTGATTGGTTCT891
AGAACCAATCAAGAAAG892
Breast CancerTTGGAAGACTTGACTGCAAATACAAACACCCAGGATCCTTTC893
Gln-1323-StopTTGATTGGTTCTTCCAAACAAATGAGGCATCAGTCTGAAAGC
CAA to TAACAGGGAGTTGTTCTGAGTGACAAGGAATTGGTTTCAG
CTGAAACCAATTCCTTGTCACTCAGACCAACTCCCTGGCTTT894
CAGACTGATGCCTCATTTGTTTGGAAGAACCAATCAAGAAAG
GATCCTGGGTGTTTGTATTTGCAGTCAAGTCTTCCAA
CTTCCAAACAAATGAGG895
CCTCATTTGTTTGGAAG896
Breast CancerCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACAAGGAATT897
Arg-1347-GlyGGTTTCAGATGATGAAGAAAGAGGAACGGGCTTGGAAGAAA
AGA to GGAATAATCAAGAAGAGCAAAGCATGGATTCAAACTTAGGTA
TACCTAAGTTTGAATCCATGCTTTGCTCTTCTTGATTATTTTCT898
TCCAAGCCCGTTCCTCTTTCTTCATCATCTGAAACCAATTCCT
TGTCACTCAGACCAACTCCCTGGCTTTCAGACTG
ATGAAGAAAGAGGAACG899
CGTTCCTCTTTCTTCAT900
Breast CancerGAAACAAGCGTCTCTGAAGACTGCTCAGGGCTATCCTCTCAG901
Gln-1395-StopAGTGACATTTTAACCACTCAGGTAAAAAGCGTGTGTGTGTGT
CAG to TAGGCACATGCGTGTGTGTGGTGTCCTTTGCATTCAGTAG
CTACTGAATGCAAAGGACACCACACACACGCATGTGCACACA902
CACACACGCTTTTTACCTGAGTGGTTAAAATGTCACTCTGAG
AGGATAGCCCTGAGCAGTCTTCAGAGACGCTTGTTTC
TAACCACTCAGGTAAAA903
TTTTACCTGAGTGGTTA904
Breast CancerTGGTGCCATTTATCGTTTTTGAAGCAGAGGGATACCATGCAA905
Gln-1408-StopCATAACCTGATAAAGCTCCAGCAGGAAATGGCTGAACTAGAA
CAG to TAGGCTGTGTTAGAACAGCATGGGTGCCAGCCTTCTAACA
TGTTAGAAGGCTGGCTCCCATGCTGTTCTAACACAGCTTCTA906
GTTCAGCCATTTCCTGCTGGAGCTTTATCAGGTTATGTTGCAT
GGTATCCCTCTGCTTCAAAAACGATAAATGGCACCA
TAAAGCTCCAGCAGGAA907
TTCCTGCTGGAGCTTTA908
Breast CancerAGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGTGACTCT909
Arg-1443-GlyTCTGCCCTTGAGGACCTGCGAAATCCAGAACAAAGCACATCA
CGA to GGAGAAAAAGGTGTGTATTGTTGGCCAAACACTGATATCT
Arg-1443-StopAGATATCAGTGTTTGGCCAACAATACACACCTTTTTCTGATGT910
CGA to TGAGCTTTGTTCTGGATTTCGCAGGTCCTCAAGGGCAGAAGAGTC
ACTTATGATGGAAGGGTAGCTGTTAGAAGGCTGGCT
AGGACCTGCGAAATCCA911
TGGATTTCGCAGGTCCT912
Breast CancerCAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT913
Ser-1512-IleGTTGATGTGGAGGAGCAACAGCTGGAAGAGTCTGGGCCACA
AGT to ATTCGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATC
GATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG914
GCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCT
TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG
AGGAGCAACAGCTGGAA915
TTCCAGCTGTTGCTCCT916
Breast CancerATCTTTCTAGGTCATCCCCTTCTAAATGCCCATCATTAGATGA917
Gln-1538-StopTAGGTGGTACATGCACAGTTGCTCTGGGAGTCTTCAGAATAG
CAG to TAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTTGT
ACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCT918
GAAGACTCCCAGAGCAACTGTGCATGTACCACCTATCATCTA
ATGATGGGCATTTAGAAGGGGATGACCTAGAAAGAT
CATGCACAGTTGCTCTG919
CAGAGCAACTGTGCATG920
Breast CancerCAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT921
Glu-1541-StopGTTGATGTGGAGGAGCAACAGCTGGAAGAGTCTGGGCCACA
GAG to TAGCGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATC
GATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG922
GCCCAGACTCTTCCAGCTGTTGCTCCTCCACATCAACAACCT
TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG
AGGAGCAACAGCTGGAA923
TTCCAGCTGTTGCTCCT924
Breast CancerAACTACCCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTG925
Thr-1561-IleGAGGAGCAACAGCTGGAAGAGTCTGGGCCACACGATTTGAC
ACC to ATCGGAAACATCTTACTTGCCAAGGCAAGATCTAGGTAATA
TATTACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAA926
ATCGTGTGGCCCAGACTCTTCCAGCTGTTGCTCCTCCACATC
AACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTT
AGCTGGAAGAGTCTGGG927
CCCAGACTCTTCCAGCT928
Breast CancerTTTGTAATTCAACATTCATCGTTGTGTAAATTAAACTTCTCCCA929
Tyr-1563-StopTTCCTTTCAGAGGGAACCCCTTACCTGGAATCTGGAATCAGC
TAC to TAGCTCTTCTCTGATGACCCTGAATCTGATCCTTCTGA
TCAGAAGGATCAGATTCAGGGTCATCAGAGAAGAGGCTGATT930
CCAGATTCCAGGTAAGGGGTTCCCTCTGAAAGGAATGGGAG
AAGTTTAATTTACACAACGATGAATGTTGAATTACAAA
AGAGGGAACCCCTTACC931
GGTAAGGGGTTCCCTCT932
Breast CancerCAACATTCATCGTTGTGTAAATTAAACTTCTCCCATTCCTTTC933
Leu-1564-ProAGAGGGAACCCCTTACCTGGAATCTGGAATCAGCCTCTTCTC
CTG to CCGTGATGACCCTGAATCTGATCCTTCTGAAGACAGAGC
GCTCTGTCTTCAGAAGGATCAGATTCAGGGTCATCAGAGAAG934
AGGCTGATTCCAGATTCCAGGTAAGGGGTTCCCTCTGAAAG
GAATGGGAGAAGTTTAATTTACACAACGATGAATGTTG
CCCTTACCTGGAATCTG935
CAGATTCCAGGTAAGGG936
Breast CancerGCCCCAGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACC937
Gln-1604-StopTCTGCATTGAAAGTTCCCCAATTGAAAGTTGCAGAATCTGCC
CAA to TAACAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTG
CAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCTGGGCA938
GATTCTGCAACTTTCAATTGGGGAACTTTCAATGCAGAGGTT
GAAGATGGTATGTTGCCAACACGAGCTGACTCTGGGGC
AAGTTCCCCAATTGAAA939
TTTCAATTGGGGAACTT940
Breast CancerGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACCTCTGCA941
Lys-1606-GluTTGAAAGTTCCCCAATTGAAAGTTGCAGAATCTGCCCAGAGT
AAA to GAACCAGCTGCTGCTCATACTACTGATACTGCTGGGTATA
TATACCCAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCT942
GGGCAGATTCTGCAACTTTCAATTGGGGAACTTTCAATGCAG
AGGTTGAAGATGGTATGTTGCCAACACGAGCTGACTC
CCCAATTGAAAGTTGCA943
TGCAACTTTCAATTGGG944
Breast CancerCAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATA945
Met-1628-ThrCTGCTGGGTATAATGCAATGGAAGAAAGTGTGAGCAGGGAG
ATG to ACGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACAA
TTGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCC946
TGCTCACACTTTCTTCCATTGCATTATACCCAGCAGTATCAGT
AGTATGAGCAGCAGCTGGACTCTGGGCAGATTCTG
TAATGCAATGGAAGAAA947
TTTCTTCCATTGCATTA948
Breast CancerGCAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGAT949
Met-1628-ValACTGCTGGGTATAATGCAATGGAAGAAAGTGTGAGCAGGGA
ATG to GTGGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACA
TGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCT950
GCTCACACTTTCTTCCATTGCATTATACCCAGCAGTATCAGTA
GTATGAGCAGCAGCTGGACTCTGGGCAGATTCTGC
ATAATGCAATGGAAGAA951
TTCTTCCATTGCATTAT952
Breast CancerCTCATACTACTGATACTGCTGGGTATAATGCAATGGAAGAAA953
Pro-1637-LeuGTGTGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAA
CCA to CTAAGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCT
AGGCCAGACACCACCATGGACATTCTTTTGTTGACCCTTTCT954
GTTGAAGCTGTCAATTCTGGCTTCTCCCTGCTCACACTTTCTT
CCATTGCATTATACCCAGCAGTATCAGTAGTATGAG
GGAGAAGCCAGAATTGA955
TCAATTCTGGCTTCTCC956
Breast CancerGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAAAGGG957
Met-1652-IleTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCTGACCCCAG
ATG to ATAAAGAATTTGTGAGTGTATCCATATGTATCTCCCTAATG
CATTAGGGAGATACATATGGATACACTCACAAATTCTTCTGG958
GGTCAGGCCAGACACCACCATGGACATTCTTTTGTTGACCCT
TTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCTGCTC
ATGTCCATGGTGGTGTC959
GACACCACCATGGACAT960
Breast CancerCACTTCCTGATTTTGTTTTCAACTTCTAATCCTTTGAGTGTTTT961
Glu-1694-StopTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGACACTGAA
GAG to TAGATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAG
CTACCCATTTTCCTCCCGCAATTCCTAGAAAATATTTCAGTGT962
CCGTTCACACACAAACTCAGCATCTGCAGAATGAAAAACACT
CAAAGGATTAGAAGTTGAAAACAAAATCAGGAAGTG
CAGATGCTGAGTTTGTG963
CACAAACTCAGCATCTG964
Breast CancerGTGTTTTTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGA965
Gly-1706-GluCACTGAAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAG
GGA to GAATTAGCTATTTCTGTAAGTATAATACTATTTCTCCCCT
AGGGGAGAAATAGTATTATACTTACAGAAATAGCTAACTACCC966
ATTTTCCTCCCGCAATTCCTAGAAAATATTTCAGTGTCCGTTC
ACACACAAACTCAGCATCTGCAGAATGAAAAACAC
TTTTCTAGGAATTGCGG967
CCGCAATTCCTAGAAAA968
Breast CancerTTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGACACTGA969
Ala-1708-GluAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTTAGCT
GCG to GAGATTTCTGTAAGTATAATACTATTTCTCCCCTCCTCCC
GGGAGGAGGGGAGAAATAGTATTATACTTACAGAAATAGCTA970
ACTACCCATTTTCCTCCCGCAATTCCTAGAAAATATTTCAGTG
TCCGTTCACACACAAACTCAGCATCTGCAGAATGAA
AGGAATTGCGGGAGGAA971
TTCCTCCCGCAATTCCT972
Breast CancerCTGAGTTTGTGTGTGAACGGACACTGAAATATTTTCTAGGAAT973
Val-1713-AlaTGCGGGAGGAAAATGGGTAGTTAGCTATTTCTGTAAGTATAA
GTA to GCATACTATTTCTCCCCTCCTCCCTTTAACACCTCAGAA
TTCTGAGGTGTTAAAGGGAGGAGGGGAGAAATAGTATTATAC974
TTACAGAAATAGCTAACTACCCATTTTCCTCCCGCAATTCCTA
GAAAATATTTCAGTGTCCGTTCACACACAAACTCAG
AAAATGGGTAGTTAGCT975
AGCTAACTACCCATTTT976
Breast CancerAACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAAT977
Trp-1718-StopGGGTAGTTAGCTATTTCTGTAAGTATAATACTATTTCTCCCCT
TGG to TAGCCTCCCTTTAACACCTCAGAATTGCATTTTTACACC
GGTGTAAAAATGCAATTCTGAGGTGTTAAAGGGAGGAGGGG978
AGAAATAGTATTATACTTACAGAAATAGCTAACTACCCATTTTC
CTCCCGCAATTCCTAGAAAATATTTCAGTGTCCGTT
CTATTTCTGTAAGTATA979
TATACTTACAGAAATAG980
Breast CancerTTCTGCTGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGG981
Glu-1725-StopTGACCCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGGTAA
GAA to TAAGTACTTGATGTTACAAACTAACCAGAGATATTCATT
AATGAATATCTCTGGTTAGTTTGTAACATCAAGTACTTACCTC982
ATTCAGCATTTTTCTTTCTTTAATAGACTGGGTCACCCCTAAA
GAGATCATAGAAAAGACAGGTTACATACAGCAGAA
CTATTAAAGAAAGAAAA983
TTTTCTTTCTTTAATAG984
Breast CancerTGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGGTGACCC985
Lys-1727-StopAGTCTATTAAAGAAAGAAAAATGCTGAATGAGGTAAGTACTTG
AAA to TAAATGTTACAAACTAACCAGAGATATTCATTCAGTCA
TGACTGAATGAATATCTCTGGTTAGTTTGTAACATCAAGTACT986
TACCTCATTCAGCATTTTTCTTTCTTTAATAGACTGGGTCACC
CCTAAAGAGATCATAGAAAAGACAGGTTACATACA
AAGAAAGAAAAATGCTG987
CAGCATTTTTCTTTCTT988
Breast CancerTCTTTCAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATG989
Pro-1749-ArgGAAGAAACCACCAAGGTCCAAAGCGAGCAAGAGAATCCCAG
CCA to CGAGACAGAAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAA
TTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGTCCTGG990
GATTCTCTTGCTCGCTTTGGACCTTGGTGGTTTCTTCCATTGA
CCACATCTCCTCTGACTTCAAAATCATGCTGAAAGA
CCAAGGTCCAAAGCGAG991
CTCGCTTTGGACCTTGG992
Breast CancerCAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGA993
Arg-1751-StopAACCACCAAGGTCCAAAGCGAGCAAGAGAATCCCAGGACAG
CGA to TGAAAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAAATCTC
GAGATTTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGT994
CCTGGGATTCTCTTGCTCGCTTTGGACCTTGGTGGTTTCTTC
CATTGACCACATCTCCTCTGACTTCAAAATCATGCTG
GTCCAAAGCGAGCAAGA995
TCTTGCTCGCTTTGGAC996
Breast CancerGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC997
Gln-1756-StopAAAGCGAGCAAGAGAATCCCAGGACAGAAAGGTAAAGCTCC
GAG to TAGCTCCCTCAAGTTGACAAAAATCTCACCCCACCACTCTGT
ACAGAGTGGTGGGGTGAGATTTTTGTCAACTTGAGGGAGGG998
AGCTTTACCTTTCTGTCCTGGGATTCTCTTGCTCGCTTTGGA
CCTTGGTGGTTTCTTCCATTGACCACATCTCCTCTGAC
GAGAATCCCAGGACAGA999
TCTGTCCTGGGATTCTC1000
Breast CancerCTCTCTTCTTCCAGATCTTCAGGGGGCTAGAAATCTGTTGCT1001
Met-1775-ArgATGGGCCCTTCACCAACATGCCCACAGGTAAGAGCCTGGGA
ATG to AGGGAACCCCAGAGTTCCAGCACCAGCCTTTGTCTTACATA
TATGTAAGACAAAGGCTGGTGCTGGAACTCTGGGGTTCTCCC1002
AGGCTCTTACCTGTGGGCATGTTGGTGAAGGGCCCATAGCA
ACAGATTTCTAGCCCCCTGAAGATCTGGAAGAAGAGAG
CACCAACATGCCCACAG1003
CTGTGGGCATGTTGGTG1004
Breast CancerAGTATGCAGATTACTGCAGTGATTTTACATCTAAATGTCCATT1005
Trp-1782-StopTTAGATCAACTGGAATGGATGGTACAGCTGTGTGGTGCTTCT
TGG to TGAGTGGTGAAGGAGCTTTCATCATTCACCCTTGGCACA
TGTGCCAAGGGTGAATGATGAAAGCTCCTTCACCACAGAAGC1006
ACCACACAGCTGTACCATCCATTCCAGTTGATCTAAAATGGA
CATTTAGATGTAAAATCACTGCAGTAATCTGCATACT
CTGGAATGGATGGTACA1007
TGTACCATCCATTCCAG1008
Breast CancerATTACTGCAGTGATTTTACATCTAAATGTCCATTTTAGATCAAC1009
Gln-1785-HisTGGAATGGATGGTACAGCTGTGTGGTGCTTCTGTGGTGAAG
CAG to CATGAGCTTTCATCATTCACCCTTGGCACAGTAAGTATT
AATACTTACTGTGCCAAGGGTGAATGATGAAAGCTCCTTCAC1010
CACAGAAGCACCACACAGCTGTACCATCCATTCCAGTTGATC
TAAAATGGACATTTAGATGTAAAATCACTGCAGTAAT
ATGGTACAGCTGTGTGG1011
CCACACAGCTGTACCAT1012
Breast CancerGTCCATTTTAGATCAACTGGAATGGATGGTACAGCTGTGTGG1013
Glu-1794-AspTGCTTCTGTGGTGAAGGAGCTTTCATCATTCACCCTTGGCAC
GAG to GATAGTAAGTATTGGGTGCCCTGTCAGAGAGGGAGGACAC
GTGTCCTCCCTCTCTGACAGGGCACCCAATACTTACTGTGCC1014
AAGGGTGAATGATGAAAGCTCCTTCACCACAGAAGCACCACA
CAGCTGTACCATCCATTCCAGTTGATCTAAAATGGAC
GTGAAGGAGCTTTCATC1015
GATGAAAGCTCCTTCAC1016
Breast CancerCTCTGCTTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGT1017
Arg-1835-StopGAGGCACCTGTGGTGACCCGAGAGTGGGTGTTGGACAGTGT
CGA to TGAAGCACTCTACCAGTGCCAGGAGCTGGACACCTACCTGA
TCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGTGCTACA1018
CTGTCCAACACCCACTCTCGGGTCACCACAGGTGCCTCACA
CATCTGCCCAATTGCTGGAGACAGAGAACACAAGCAGAG
TGGTGACCCGAGAGTGG1019
CCACTCTCGGGTCACCA1020
Breast CancerTTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCA1021
Trp-1837-ArgCCTGTGGTGACCCGAGAGTGGGTGTTGGACAGTGTAGCACT
TGG to CGGCTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCC
GGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGT1022
GCTACACTGTCCAACACCCACTCTCGGGTCACCACAGGTGC
CTCACACATCTGCCCAATTGCTGGAGACAGAGAACACAA
CCCGAGAGTGGGTGTTG1023
CAACACCCACTCTCGGG1024
Breast CancerTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCAC1025
Trp-1837-StopCTGTGGTGACCCGAGAGTGGGTGTTGGACAGTGTAGCACTC
TGG to TAGTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCCA
TGGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAG1026
TGCTACACTGTCCAACACCCACTCTCGGGTCACCACAGGTG
CCTCACACATCTGCCCAATTGCTGGAGACAGAGAACACA
CCGAGAGTGGGTGTTGG1027
CCAACACCCACTCTCGG1028
|
[0128]
16
TABLE 15
|
|
|
BRCA2 Mutations and Genome-Correcting Oligos
|
Clinical Phenotype &
SEQ ID
|
Mutation
Correcting Oligos
NO:
|
|
Breast cancer
GTTAAAACTAAGGTGGGATTTTTTTTTTAAATAGATTTAGGAC
1029
|
PHE32LEU
CAATAAGTCTTAATTGGTTTGAAGAACTTTCTTCAGAAGCTCC
|
TTT to CTT
ACCCTATAATTCTGAACCTGCAGAAGAATCTGAAC
|
GTTCAGATTCTTCTGCAGGTTCAGAATTATAGGGTGGAGCTT
1030
|
CTGAAGAAAGTTCTTCAAACCAATTAAGACTTATTGGTCCTAA
|
ATCTATTTAAAAAAAAAATCCCACCTTAGTTTTAAC
|
TTAATTGGTTTGAAGAA
1031
|
TTCTTCAAACCAATTAA
1032
|
|
Breast cancer
TAGATTTAGGACCAATAAGTCTTAATTGGTTTGAAGAACTTTC
1033
|
TYR42CYS
TTCAGAAGCTCCACCCTATAATTCTGAACCTGCAGAAGAATC
|
TAT to TGT
TGAACATAAAAACAACAATTACGAACCAAACCTATT
|
AATAGGTTTGGTTCGTAATTGTTGTTTTTATGTTCAGATTCTTC
1034
|
TGCAGGTTCAGAATTATAGGGTGGAGCTTCTGAAGAAAGTTC
|
TTCAAACCAATTAAGACTTATTGGTCCTAAATCTA
|
TCCACCCTATAATTCTG
1035
|
CAGAATTATAGGGTGGA
1036
|
|
Breast cancer
AAGAACTTTCTTCAGAAGCTCCACCCTATAATTCTGAACCTGC
1037
|
LYS53ARG
AGAAGAATCTGAACATAAAAACAACAATTACGAACCAAACCTA
|
AAA to AGA
TTTAAAACTCCACAAAGGAAACCATCTTATAATCA
|
TGATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAGGTTTG
1038
|
GTTCGTAATTGTTGTTTTTATGTTCAGATTCTTCTGCAGGTTC
|
AGAATTATAGGGTGGAGCTTCTGAAGAAAGTTCTT
|
TGAACATAAAAACAACA
1039
|
TGTTGTTTTTATGTTCA
1040
|
|
Breast cancer
CTATTTAAAACTCCACAAAGGAAACCATCTTATAATCAGCTGG
1041
|
Phe81Leu
CTTCAACTCCAATAATATTCAAAGAGCAAGGGCTGACTCTGC
|
TTC to CTC
CGCTGTACCAATCTCCTGTAAAAGAATTAGATAAAT
|
ATTTATCTAATTCTTTTACAGGAGATTGGTACAGCGGCAGAGT
1042
|
CAGCCCTTGCTCTTTGAATATTATTGGAGTTGAAGCCAGCTG
|
ATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAG
|
CAATAATATTCAAAGAG
1043
|
CTCTTTGAATATTATTG
1044
|
|
Breast cancer
GTCAGACACCAAAACATATTTCTGAAAGTCTAGGAGCTGAGG
1045
|
TRP194TERM
TGGATCCTGATATGTCTTGGTCAAGTTCTTTAGCTACACCACC
|
TGG to TAG
CACCCTTAGTTCTACTGTGCTCATAGGTAATAATAG
|
CTATTATTACCTATGAGCACAGTAGAACTAAGGGTGGGTGGT
1046
|
GTAGCTAAAGAACTTGACCAAGACATATCAGGATCCACCTCA
|
GCTCCTAGACTTTCAGAAATATGTTTTGGTGTCTGAC
|
TATGTCTTGGTCAAGTT
1047
|
AACTTGACCAAGACATA
1048
|
|
Breast cancer
CTGAAAGTCTAGGAGCTGAGGTGGATCCTGATATGTCTTGGT
1049
|
PRO201ARG
CAAGTTCTTTAGCTACACCACCCACCCTTAGTTCTACTGTGCT
|
CCA to CGA
CATAGGTAATAATAGCAAATGTGTATTTACAAGAAA
|
TTTCTTGTAAATACACATTTGCTATTATTACCTATGAGCACAGT
1050
|
AGAACTAAGGGTGGGTGGTGTAGCTAAAGAACTTGACCAAGA
|
CATATCAGGATCCACCTCAGCTCCTAGACTTTCAG
|
AGCTACACCACCCACCC
1051
|
GGGTGGGTGGTGTAGCT
1052
|
|
Breast cancer
ACAATACACATAAATTTTTATCTTACAGTCAGAAATGAAGAAG
1053
|
Pro222Ser
CATCTGAAACTGTATTTCCTCATGATACTACTGCTGTAAGTAA
|
CCT to TCT
ATATGACATTGATTAGACTGTTGAAATTGCTAACA
|
TGTTAGCAATTTCAACAGTCTAATCAATGTCATATTTACTTACA
1054
|
GCAGTAGTATCATGAGGAAATACAGTTTCAGATGCTTCTTCAT
|
TTCTGACTGTAAGATAAAAATTTATGTGTATTGT
|
CTGTATTTCCTCATGAT
1055
|
ATCATGAGGAAATACAG
1056
|
|
Breast cancer
AATGGTCTCAACTAACCCTTTCAGGTCTAAATGGAGCCCAGA
1057
|
Leu-414-Term
TGGAGAAAATACCCCTATTGCATATTTCTTCATGTGACCAAAA
|
TTG to TAG
TATTTCAGAAAAAGACCTATTAGACACAGAGAACAA
|
TTGTTCTCTGTGTCTAATAGGTCTTTTTCTGAAATATTTTGGTC
1058
|
ACATGAAGAAATATGCAATAGGGGTATTTTCTCCATCTGGGC
|
TCCATTTAGACCTGAAAGGGTTAGTTGAGACCATT
|
ACCCCTATTGCATATTT
1059
|
AAATATGCAATAGGGGT
1060
|
|
Breast cancer,male
AGCCTCTGAAAGTGGACTGGAAATACATACTGTTTGCTCACA
1061
|
Cys554Trp
GAAGGAGGACTCCTTATGTCCAAATTTAATTGATAATGGAAG
|
TGT to TGG
CTGGCCAGCCACCACCACACAGAATTCTGTAGCTTTG
|
CAAAGCTACAGAATTCTGTGTGGTGGTGGCTGGCCAGCTTC
1062
|
CATTATCAATTAAATTTGGACATAAGGAGTCCTCCTTCTGTGA
|
GCAAACAGTATGTATTTCCAGTCCACTTTCAGAGGCT
|
TCCTTATGTCCAAATTT
1063
|
AAATTTGGACATAAGGA
1064
|
|
Breast cancer
AACTCTACCATGGTTTTATATGGAGACACAGGTGATAAACAA
1065
|
Lys944Term
GCAACCCAAGTGTCAATTAAAAAAGATTTGGTTTATGTTCTTG
|
AAA to TAA
CAGAGGAGAACAAAAATAGTGTAAAGCAGCATATAA
|
TTATATGCTGCTTTACACTATTTTTGTTCTCCTCTGCAAGAAC
1066
|
ATAAACCAAATCTTTTTTAATTGACACTTGGGTTGCTTGTTTAT
|
CACCTGTGTCTCCATATAAAACCATGGTAGAGTT
|
TGTCAATTAAAAAAGAT
1067
|
ATCTTTTTTAATTGACA
1068
|
|
Breast cancer,male
ATGACTACTGGCACTTTTGTTGAAGAAATTACTGAAAATTACA
1069
|
Glu1320Term
AGAGAAATACTGAAAATGAAGATAACAAATATACTGCTGCCAG
|
GAA to TAA
TAGAAATTCTCATAACTTAGAATTTGATGGCAGTG
|
CACTGCCATCAAATTCTAAGTTATGAGAATTTCTACTGGCAGC
1070
|
AGTATATTTGTTATCTTCATTTTCAGTATTTCTCTTGTAATTTTC
|
AGTAATTTCTTCAACAAAAGTGCCAGTAGTCAT
|
CTGAAAATGAAGATAAC
1071
|
GTTATCTTCATTTTCAG
1072
|
|
Breast cancer
CATGAAACAATTAAAAAAGTGAAAGACATATTTACAGACAGTT
1073
|
Glu1876Term
TCAGTAAAGTAATTAAGGAAAACAACGAGAATAAATCAAAAAT
|
GAA to TAA
TTGCCAAACGAAAATTATGGCAGGTTGTTACGAGG
|
CCTCGTAACAACCTGCCATAATTTTCGTTTGGCAAATTTTTGA
1074
|
TTTATTCTCGTTGTTTTCCTTAATTACTTTACTGAAACTGTCTG
|
TAAATATGTCTTTCACTTTTTTAATTGTTTCATG
|
TAATTAAGGAAAACAAC
1075
|
GTTGTTTTCCTTAATTA
1076
|
|
Breast cancer
TGAAAGACATATTTACAGACAGTTTCAGTAAAGTAATTAAGGA
1077
|
Ser1882Term
AAACAACGAGAATAAATCAAAAATTTGCCAAACGAAAATTATG
|
TCA to TAA
GCAGGTTGTTACGAGGCATTGGATGATTCAGAGGA
|
TCCTCTGAATCATCCAATGCCTCGTAACAACCTGCCATAATTT
1078
|
TCGTTTGGCAAATTTTTGATTTATTCTCGTTGTTTTCCTTAATT
|
ACTTTACTGAAACTGTCTGTAAATATGTCTTTCA
|
GAATAAATCAAAAATTT
1079
|
AAATTTTTGATTTATTC
1080
|
|
Breast cancer
AACCAAAATATGTCTGGATTGGAGAAAGTTTCTAAAATATCAC
1081
|
Glu1953Term
CTTGTGATGTTAGTTTGGAAATTCAGATATATGTAAATGTAG
|
GAA to TAA
TATAGGGAAGCTTCATAAGTCAGTCTCATCTGCAA
|
TTGCAGATGAGACTGACTTATGAAGCTTCCCTATACTACATTT
1082
|
ACATATATCTGAAGTTTCCAAACTAACATCACAAGGTGATATT
|
TTAGAAACTTTCTCCAATCCAGACATATTTTGGTT
|
TTAGTTTGGAAACTTCA
1083
|
TGAAGTTTCCAAACTAA
1084
|
|
Breast cancer
TTAGTTTGGAAACTTCAGATATATGTAAATGTAGTATAGGGAA
1085
|
Ser1970Term
GCTTCATAAGTCAGTCTCATCTGCAAATACTTGTGGGATTTTT
|
TCA to TAA
AGCACAGCAAGTGGAAAATCTGTCCAGGTATCAGA
|
TCTGATACCTGGACAGATTTTCCACTTGCTGTGCTAAAAATCC
1086
|
CACAAGTATTTGCAGATGAGACTGACTTATGAAGCTTCCCTAT
|
ACTACATTTACATATATCTGAAGTTTCCAAACTAA
|
GTCAGTCTCATCTGCAA
1087
|
TTGCAGATGAGACTGAC
1088
|
|
Breast cancer
AAGTCAGTCTCATCTGCAAATACTTGTGGGATTTTTAGCACAG
1089
|
Gln1987Term
CAAGTGGAAAATCTGTCCAGGTATCAGATGCTTCATTACAAAA
|
CAG to TAG
CGCAAGACAAGTGTTTTCTGAAATAGAAGATAGTA
|
TACTATCTTCTATTTCAGAAAACACTTGTCTTGCGTTTTGTAAT
1090
|
GAAGCATCTGATACCTGGACAGATTTTCCACTTGCTGTGCTA
|
AAAATCCCACAAGTATTTGCAGATGAGACTGACTT
|
AATCTGTCCAGGTATCA
1091
|
TGATACCTGGACAGATT
1092
|
|
Breast cancer
AAAATAAGATTAATGACAATGAGATTCATCAGTTTAACAAAAA
1093
|
Ala2466Val
CAACTCCAATCAAGCAGCAGCTGTAACTTTCACAAAGTGTGA
|
GCA to GTA
AGAAGAACCTTTAGGTATTGTATGACAATTTGTGTG
|
CACACAAATTGTCATACAATACCTAAAGGTTCTTCTTCACACT
1094
|
TTGTGAAAGTTACAGCTGCTGCTTGATTGGAGTTGTTTTTGTT
|
AAACTGATGAATCTCATTGTCATTAATCTTATTTT
|
TCAAGCAGCAGCTGTAA
1095
|
TTACAGCTGCTGCTTGA
1096
|
|
Breast cancer
AGGCAACGCGTCTTTCCACAGCCAGGCAGTCTGTATCTTGCA
1097
|
Arg2520Term
AAAACATCCACTCTGCCTCGAATCTCTCTGAAAGCAGCAGTA
|
CGA to TGA
GGAGGCCAAGTCCCCTCTGCGTGTCCTCATAAACAGG
|
CCTGTTTATGAGGACACGCAGAGGGGACTTGGCCTCCTACT
1098
|
GCTGCTTTCAGAGAGATTCGAGGCAGAGTGGATGTTTTTGCA
|
AGATACAGACTGCCTGGCTGTGGAAAGACGCGTTGCCT
|
CTCTGCCTCGAATCTCT
1099
|
AGAGATTCGAGGCAGAG
1100
|
|
Breast cancer
ATTTCATTGAGCGCAAATATATCTGAAACTTCTAGCAATAAAA
1101
|
Gln2714Term
CTAGTAGTGCAGATACCCAAAAAGTGGCCATTATTGAACTTA
|
CAA to TAA
CAGATGGGTGGTATGCTGTTAAGGCCCAGTTAGATC
|
GATCTAACTGGGCCTTAACAGCATACCACCCATCTGTAAGTT
1102
|
CAATAATGGCCACTTTTTGGGTATCTGCACTACTAGTTTTATT
|
GCTAGAAGTTTCAGATATATTTGCGCTCAATGAAAT
|
CAGATAGCCCAAAAAGTG
1103
|
CACTTTTTGGGTATCTG
1104
|
|
Breast cancer
CAGAACTGGTGGGCTCTCCTGATGCCTGTACACCTCTTGAAG
1105
|
Leu2776Term
CCCCAGAATCTCTTATGTTAAAGGTAAATTAATTTGCACTCTT
|
TTA to TGA
GGTAAAAATCAGTCATTGATTCAGTTAAATTCTAGA
|
TCTAGAATTTAACTGAATCAATGACTGATTTTTACCAAGAGTG
1106
|
CAAATTAATTTACCTTTAACATAAGAGATTCTGGGGCTTCAAG
|
AGGTGTACAGGCATCAGGAGAGCCCACCAGTTCTG
|
TCTTATGTTAAAGATTT
1107
|
AAATCTTTAACATAAGA
1108
|
|
Breast cancer
CCTTTTGTTTTCTTAGAAAACACAACAAAACCATATTTACCATC
1109
|
Gln2893Term
ACGTGCACTAACAAGACAGCAAGTTCGTGCTTTGCAAGATGG
|
CAG to TAG
TGCAGAGCTTTATGAAGCAGTGAAGAATGCAGCAG
|
CTGCTGCATTCTTCACTGCTTCATAAAGCTCTGCACCATCTTG
1110
|
CAAAGCACGAACTTGCTGTCTTGTTAGTGCACGTGATGGTAA
|
ATATGGTTTTGTTGTGTTTTCTAAGAAAACAAAAGG
|
TAACAAGACAGCAAGTT
1111
|
AACTTGCTGTCTTGTTA
1112
|
|
Breast cancer
AATCACAGGCAAATGTTGAATGATAAGAAACAAGCTCAGATC
1113
|
Ala2951Thr
CAGTTGGAAATTAGGAAGGCCATGGAATCTGCTGAACAAAAG
|
GCC to ACC
GAACAAGGTTTATCAAGGGATGTCACAACCGTGTGGA
|
TCCACACGGTTGTGACATCCCTTGATAAACCTTGTTCCTTTTG
1114
|
TTCAGCAGATTCCATGGCCTTCCTAATTTCCAACTGGATCTGA
|
GCTTGTTTCTTATCATTCAACATTTGCCTGTGATT
|
TTAGGAAGGCCATGGAA
1115
|
TTCCATGGCCTTCCTAA
1116
|
|
Breast cancer
ACAATTTACTGGCAATAAAGTTTTGGATAGACCTTAATGAGGA
1117
|
Met3118Thr
CATTATTAAGCCTCATATGTTAATTGCTGCAAGCAACCTCCAG
|
ATG to ACG
TGGCGACCAGAATCCAAATCAGGCCTTCTTACTTT
|
AAAGTAAGAAGGGGTGATTTGGATTGTGGTGGCGAGTGGAG
1118
|
GTTGCTTGCAGCAATTAACATATGAGGCTTAATAATGTCCTCA
|
TTAAGGTGTATGGAAAAGTTTATTGGGAGTAAATTGT
|
GCCTCATATGTTAATTG
1119
|
CAATTAACATATGAGGC
1120
|
|
Breast cancer
GACTGAAACGACGTTGTACTACATCTCTGATCAAAGAACAGG
1121
|
Thr3401Met
AGAGTTCCCAGGCCAGTACGGAAGAATGTGAGAAAAATAAGC
|
ACG to ATG
AGGACACAATTACAACTAAAAAATATATCTAAGCATT
|
AATGCTTAGATATATTTTTTAGTTGTAATTGTGTCCTGCTTATT
1122
|
TTTCTCACATTCTTCCGTACTGGCCTGGGAACTCTCCTGTTCT
|
TTGATCAGAGATGTAGTACAACGTCGTTTCAGTC
|
GGCCAGTACGGAAGAAT
1123
|
ATTCTTCCGTACTGGCC
1124
|
|
Breast cancer
AAAGAACAGGAGAGTTCCCAGGCCAGTACGGAAGAATGTGA
1125
|
Ile3412Val
GAAAAATAAGCAGGACACAATTACAACTAAAAAATATATCTAA
|
ATT to GTT
GCATTTGCAAAGGCGACAATAAATTATTGACGCTTAA
|
TTAAGCGTCAATAATTTATTGTCGCCTTTGCAAATGCTTAGAT
1126
|
ATATTTTTTAGTTGTAATTGTGTCCTGCTTATTTTTCTCACATT
|
CTTCCGTACTGGCCTGGGAACTCTCCTGTTCTTT
|
AGGACACAATTACAACT
1127
|
AGTTGTAATTGTGTCCT
1128
|
|
EXAMPLE 9
[0129] Cystic Fibrosis—CFTR
[0130] Cystic fibrosis is a lethal disease affecting approximately one in 2,500 live Caucasian births and is the most common autosomal recessive disease in Caucasians. Patients with this disease have reduced chloride ion permeability in the secretory and absorptive cells of organs with epithelial cell linings, including the airways, pancreas, intestine, sweat glands and male genital tract. This, in turn, reduces the transport of water across the epithelia. The lungs and the GI tract are the predominant organ systems affected in this disease and the pathology is characterized by blocking of the respiratory and GI tracts with viscous mucus. The chloride impermeability in affected tissues is due to mutations in a specific chloride channel, the cystic fibrosis transmembrane conductance regulator protein (CFTR), which prevents normal passage of chloride ions through the cell membrane (Welsh et al., Neuron, 8:821-829 (1992)). Damage to the lungs due to mucus blockage, frequent bacterial infections and inflammation is the primary cause of morbidity and mortality in CF patients and, although maintenance therapy has improved the quality of patients' lives, the median age at death is still only around 30 years. There is no effective treatment for the disease, and therapeutic research is focused on gene therapy using exogenous transgenes in viral vectors and/or activating the defective or other chloride channels in the cell membrane to normalize chloride permeability (Tizzano et al., J. Pediat., 120:337-349 (1992)). However, the death of a teenage patent treated with an adenovirus vector carrying an exogenous CFTR gene in clinical trials in the late 1990's has impacted this area of research.
[0131] The oligonucleotides of the invention for correction of the CFTR gene are attached as a table.
17TABLE 16
|
|
CFTR Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Cystic fibrosisAAGGATACAGACAGCGCCTGGAATTGTCAGACATATACCAAA1129
Ala46AspTCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGA
GCT to GATAAGGTATGTTCATGTACATTGTTTAGTTGAAGAGAG
CTCTCTTCAACTAAACAATGTACATGAACATACCTTTCCAATTT1130
TTCAGATAGATTGTCAGCAGAATCAACAGAAGGGATTTGGTA
TATGTCTGACAATTCCAGGCGCTGTCTGTATCCTT
TGATTCTGCTGACAATC1131
GATTGTCAGCAGAATCA1132
|
Cystic fibrosisAGCGCCTGGAATTGTCAGACATATACCAAATCCCTTCTGTTG1133
Ser50TyrATTCTGCTGACAATCTATCTGAAAAATVGGAAAGGTATGTTCA
TCT to TATTGTACATTGTTTAGTTGAAGAGAGAAATTCATATTA
TAATATGAATTTCTCTCTTCAACTAAACAATGTACATGAACATA1134
CCTTTCCAATTTTTCAGATAGATTGTCAGCAGAATCAACAGAA
GGGATTTGGTATATGTCTGACAATTCCAGGCGCT
CAATCTATCTGAAAAAT1135
ATTTTTCAGATAGATTG1136
|
Congenital absence ofAGGACAACTAAAATATTTGCACATGCAACTTATTGGTCCCACT1137
vas deferensTTTTATTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAA
Glu56LysGAAAAATCCTAAACTCATTAATGCCCTTCGGCGAT
GAA-AAAATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGC1138
CAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGA
CCAATAAGTTGCATGTGCAAATATTTTAGTTGTCCT
TTTGCAGAGAATGGGAT1139
ATCCCATTCTCTGCAAA1140
|
Cystic fibrosisAGGACAACTAAAATATTTGCACATGCAACTTATTGGTCCCACT1141
Trp57GlyTTTTATTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAA
TGG to GGGGAAAAATCCTAAACTCATTAATGCCCTTCGGCGAT
ATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGC1142
CAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGA
CCAATAAGTTGCATGTGCAAATATTTTAGTTGTCCT
TTTGCAGAGAATGGGAT1143
ATCCCATTCTCTGCAAA1144
|
Cystic fibrosisAACTAAAATATTTGCACATGCAACTTATTGGTCCCACTTTTTAT1145
Trp57TermTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAA
TGG to TGAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTT
AAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTT1146
GAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGT
GGGACCAATAAGTTGCATGTGCAAATATTTTAGTT
AGAGAATGGGATAGAGA1147
TCTCTATCCCATTCTCT1148
|
Congenital absence ofACTAAAATATTTGCACATGCAACTTATTGGTCCCACTTTTTATT1149
vas deferensCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAA
Asp58AsnTCCTAAACTCATTAATGCCCTTCGGCGATGTTTTT
GAT to AATAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTT1150
TGAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAG
TGGGACCAATAAGTTGCATGTGCAAATATTTTAGT
GAGAATGGGATAGAGAG1151
CTCTCTATCCCATTCTC1152
|
Cystic fibrosisATATTTGCACATGCAACTTATTGGTCCCACTTTTTATTCTTTTG1153
Glu60TermCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAA
GAG to TAGACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGA
TCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGAT1154
TTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAA
TAAAAAGTGGGACCAATAAGTTGCATGTGCAAATAT
GGGATAGAGAGCTGGCT1155
AGCCAGCTCTCTATCCC1156
|
Cystic fibrosisGGTCCCACTTTTTATTCTTTTGCAGAGAATGGGATAGAGAGC1157
Pro67LeuTGGCTTCAAAGAAAAATCCTAAACTCATTAATGCCCTTCGGC
CCT to CTTGATGTTTTTTCTGGAGATTTATGTTCTATGGAATCTT
AAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAA1158
GGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCT
ATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACC
GAAAAATCCTAAACTCA1159
TGAGTTTAGGATTTTTC1160
|
Cystic fibrosisTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCT1161
Arg74TrpAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTA
CGG to TGGTGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGA
TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT1162
CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATT
TTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCA
ATGCCCTTCGGCGATGT1163
ACATCGCCGAAGGGCAT1164
|
Congenital absence ofGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC1165
vas deferensTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTT
ARG75GLNCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC
CGA to CAAGAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA1166
ATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAG
GATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC
CCTTCGGCGATGTTTTT1167
AAAAACATCGCCGAAGG1168
|
Cystic fibrosisGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC1169
Arg75LeuTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTT
CGA to CTACTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC
GAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA1170
ATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAG
GATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC
CCTTCGGCGATGTTTTT1171
AAAAACATCGCCGAAGG1172
|
Cystic fibrosisAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAA1173
Arg75TermCTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGT
CGA to TGATCTATGGAATCTTTTTATATTTAGGGGTAAGGATCT
AGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAA1174
TCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGG
ATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCT
CCCTTCGGCGATGTTTT1175
AAAACATCGCCGAAGGG1176
|
Cystic fibrosisAAAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG1177
Gly85GluGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGG
GGA to GAAATCTCATTTGTACATTCATTATGTATCACATAACT
AGTTATGTGATACATAATGAATGTACAAATGAGATCCTTACCC1178
CTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAA
ACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT
GTTCTATGGAATCTTTT1179
AAAAGATTCCATAGAAC1180
|
Cystic fibrosisAAAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG1181
Gly85ValGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGG
GGA to GTAATCTCATTTGTACATTCATTATGTATCACATAACT
AGTTATGTGATACATAATGAATGTACAAATGAGATCCTTACCC1182
CTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAA
ACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT
GTTCTATGGAATCTTTT1183
AAAAGATTCCATAGAAC1184
|
Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT1185
Leu88SerGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT
TTA to TCAGTACATTCATTATGTATCACATAACTATATGCATT
AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA1186
TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT
CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT
AATCTTTTTATATTTAG1187
CTAAATATAAAAAGATT1188
|
Cystic fibrosisCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGAT1189
Phe87LeuTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC
TTT to CTTATTTGTACATTCATTATGTATCACATAACTATATG
CATATAGTTATGTGATACATAATGAATGTACAAATGAGATCCT1190
TACCCCTAAATATAAAAAGATTCCATAGAACATAAATCTCCAG
AAAAAACATCGCCGAAGGGCATTAATGAGTTTAGG
ATGGAATCTTTTTATAT1191
ATATAAAAAGATTCCAT1192
|
Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT1193
Leu88TermGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT
TTA to TGAGTACATTCATTATGTATCACATAACTATATGCATT
AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA1194
TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT
CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT
AATCTTTTTATATTTAG1195
CTAAATATAAAAAGATT1196
|
Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT1197
Leu88TermGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT
TTA to TAAGTACATTCATTATGTATCACATAACTATATGCATT
AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA1198
TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT
CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT
AATCTTTTTATATTTAG1199
CTAAATATAAAAAGATT1200
|
Cystic fibrosisAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTTCTATG1201
Gly91ArgGAATCTTTTTATATTTAGGGGTAAGGATCTCATTTGTACATTC
GGG to AGGATTATGTATCACATAACTATATGCATTTTTGTGAT
ATCACAAAAATGCATATAGTTATGTGATACATAATGAATGTAC1202
AAATGAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAAC
ATAAATCTCCAGAAAAAACATCGCCGAAGGGCATT
TATATTTAGGGGTAAGG1203
CCTTACCCCTAAATATA1204
|
Cystic fibrosisAATAAATGAAATTTAATTTCTCTGTTTTTCCCCTTTTGTAGGAA1205
Gln98ArgGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCATA
CAG to CGGGCTTCCTATGACCCGGATAACAAGGAGGAACGCTC
GAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATT1206
CTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTAC
AAAAGGGGAAAAACAGAGAAATTAAATTTCATTTATT
AGCAGTACAGCCTCTCT1207
AGAGAGGCTGTACTGCT1208
|
Cystic fibrosisAAATAAATGAAATTTAATTTCTCTGTTTTTCCCCTTTTGTAGGA1209
Gln98TermAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCAT
CAG-TAGAGCTTCCTATGACCCGGATAACAAGGAGGAACGCT
AGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTC1210
TTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACA
AAAGGGGAAAAACAGAGAAATTAAATTTCATTTATTT
AAGCAGTACAGCCTCTC1211
GAGAGGCTGTACTGCTT1212
|
Cystic fibrosisCCCTTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTAC1213
Ser108PheTGGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGG
TCC to TTCAACGCTCTATCGCGATTTATCTAGGCATAGGCTTATG
CATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCC1214
TTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAG
AGAGGCTGTACTGCTTTGGTGACTTCCTACAAAAGGG
CATAGCTTCCTATGACC1215
GGTCATAGGAAGCTATG1216
|
Cystic fibrosisTTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGG1217
Tyr109CysGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGAAC
TAT to TGTGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCT
AGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCC1218
TCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGT
AAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAAAA
AGCTTCCTATGACCCGG1219
CCGGGTCATAGGAAGCT1220
|
Cystic fibrosisTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGA1221
Asp110HisAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGAACGC
GAC to CACTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTC
GAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTT1222
CCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCA
GTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAA
CTTCCTATGACCCGGAT1223
ATCCGGGTCATAGGAAG1224
|
Congenital absence ofAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAA1225
vas deferensTCATAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCTA
Pro111LeuTCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTT
CCG to CTGAAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAG1226
CGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTT
CCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCT
CTATGACCCGGATAACA1227
TGTTATCCGGGTCATAG1228
|
Cystic fibrosisGTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGAC1229
Arg117CysCCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGC
CGC to TGCATAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGC
GCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCTA1230
GATAAATCGCGATAGAGCGCCTCCTTGTTATCCGGGTCAT
AGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTAC
AGGAGGAACGCTCTATC1231
GATAGAGCGTTCCTCCT1232
|
Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC1233
Arg117HisCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA
CGC to CACTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT
AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT1234
AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCA
TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA
GGAGGAACGCTCTATCG1235
CGATAGAGCGTTCCTCC1236
|
Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC1237
Arg117LeuCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA
CGC to CTCTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT
AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT1238
AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCA
TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA
GGAGGAACGCTCTATCG1239
CGATAGAGCGTTCCTCC1240
|
Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC1241
Arg117ProCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA
CGC to CCCTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT
AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT1242
AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCA
TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA
GGAGGAACGCTCTATCG1243
CGATAGAGCGTTCCTCC1244
|
Cystic fibrosisCTCTTACTGGGAAGAATCATAGCTTCCTATGACCCGGATAAC1245
Ala120ThrAAGGAGGAACGCTCTATCGCGATTTATCTAGGCATAGGCTTA
GCG-ACGTGCCTTCTCTTTATTGTGAGGACACTGCTCCTACACC
GGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGCATAAG1246
CCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCCTTGTTA
TCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAG
GCTCTATCGCGATTTAT1247
ATAAATCGCGATAGAGC1248
|
Cystic fibrosisGGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGA1249
Tyr122TermACGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTCT
TAT to TAACTTTATTGTGAGGACACTGCTCCTACACCCAGCCATT
AATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAA1250
GGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCT
CCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCC
GCGATTTATCTAGGCAT1251
ATGCCTAGATAAATCGC1252
|
Cystic fibrosisTAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCTATCG1253
Gly126AspCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAG
GGC-GACGACACTGCTCCTACACCCAGCCATTTTTGGCCTTCA
TGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCAC 1254
AATAAAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGAT
AGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTA
AGGCATAG_E,UNS GCTTATGCC1255
GGCATAAGCCTATGCCT1256
|
Cystic fibrosisTCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGT1257
His139ArgGAGGACACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCA
CAC to CGCCATTGGAATGCAGATGAGAATAGCTATGTTTAGTTT
AAACTAAACATAGCTATTCTCATCTGCATTCCAATGTGATGAA1258
GGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATA
AAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGA
GCTCCTACACCCAGCCA1259
TGGCTGGGTGTAGGAGC1260
|
Cystic fibrosisTTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAGGAC1261
Ala141AspACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCACATTGG
GCC to GACAATGCAGATGAGAATAGCTATGTTTAGTTTGATTTA
TAAATCAAACTAAACATAGCTATTCTCATCTGCATTCCAATGT1262
GATGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTC
ACAATAAAGAGAAGGCATAAGCCTATGCCTAGATAAA
ACACCCAGCCATTTTTG1263
CAAAAATGGCTGGGTGT1264
|
Cystic fibrosisGCCTTCTCTTTATTGTGAGGACACTGCTCCTACACCCAGCCA1265
Ile148ThrTTTTTGGCCTTCATCACATTGGAATGCAGATGAGAATAGCTAT
ATT to ACTGTTTAGTTTGATTTATAAGAAGGTAATACTTCCTTG
CAAGGAAGTATTACCTTCTTATAAATCAAACTAAACATAGCTA1266
TTCTCATCTGCATTCCAATGTGATGAAGGCCAAAAATGGCTG
GGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGC
TCATCACATTGGAATGC1267
GCATTCCAATGTGATGA1268
|
Cystic fibrosisCTTCTCTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTT1269
Gly149ArgTTGGCCTTCATCACATTGGAATGCAGATGAGAATAGCTATGTT
GGA to AGATAGTTTGATTTATAAGAAGGTAATACTTCCTTGCA
TGCAAGGAAGTATTACCTTCTTATAAATCAAACIAAACATAGC1270
TATTCTCATCTGCATTCCAATGTGATGAAGGCCAAAAATGGCT
GGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAG
ATCACATTGGAATGCAG1271
CTGCATTCCAATGTGAT1272
|
Cystic fibrosisTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTTTTGGC1273
Gln151TermCTTCATCACATTGGAATGCAGATGAGAATAGCTATGTTTAGTT
CAG to TAGTGATTTATAAGAAGGTAATACTTCCTTGCACAGGCC
GGCCTGTGCAAGGAAGTATTACCTTCTTATAAATCAAACTAAA1274
CATAGCTATTCTCATCTGCATTCCAATGTGATGAAGGCCAAAA
ATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAA
TTGGAATGCAGATGAGA1275
TCTCATCTGCATTCCAA1276
|
Cystic fibrosisAATATATTTGTATTTTGTTTGTTGAAATTATCTAACTTTCCATTT1277
Lys166GluTTCTTTTAGACTTTAAAGCTGTCAAGCCGTGTTCTAGATAAAA
AAG-GAGTAAGTATTGGACAACTTGTTAGTCTCCTTTCCA
TGGAAAGGAGACTAACAAGTTGTCCAATACTTATTTATCTAG1278
AACACGGCTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAA
GTTAGATAATTTCAACAAACAAAATACAAATATATT
AGACTTTAAAGCTGTCA1279
TGACAGCTTTAAAGTCT1280
|
Cystic fibrosisTTATCTAACTTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAG1281
Ile175ValCCGTGTTCTAGATAAAATAAGTATTGGACAACTTGTTAGTCTC
ATA-GTACTTTCCAACAACCTGAACAAATTTGATGAAGTAT
ATACTTCATCAAATTTGTTCAGGTTGTTGGAAAGGAGACTAAC1282
AAGTTGTCCAATACTTATTTTATCTAGAACACGGCTTGACAGC
TTTAAAGTCTAAAAGAAAAATGGAAAGTTAGATAA
TAGATAAAEATAAGTATT1283
AATACTTATTTTATCTA1284
|
Cystic fibrosisTTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAGCCGTGTTCT1285
Gly178ArgAGATAAAATAAGTATTGGACAACTTGTTAGTCTCCTTTCCAAC
GGA to AGAAACCTGAACAAATTTGATGAAGTATGTACCTATT
AATAGGTACATACTTCATCAAATTTGTTCAGGTTGTTGGAAAG1286
GAGACTAACAAGTTGTCCAATACTTATTTTATCTAGAACACGG
CTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAA
TAAGTATTGGACAACTT1287
AAGTTGTCCAATACTTA1288
|
Cystic fibrosisAAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCCAG1289
His199GlnGGACTTGCATTGGCACATTTCGTGTGGATCGCTCCTTTGCAA
CAT to CAGGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTTA
TAACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAA1290
AGGAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGA
AAATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTT
TTGGCACATTTCGTGTG1291
CACACGAAATGTGCCAA1292
|
Cystic fibrosisGGAAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCC1293
His199TyrAGGGACTTGCATTGGCACATTTCGTGTGGATCGCTCCAAGC
CAT to TATAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGT
ACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAG1294
GAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGAAA
ATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTTCC
CATTGGCACATTTCGTG1295
CACGAAATGTGCCAATG1296
|
Cystic fibrosisTGTTTTTGCTGTGCTTTTATTTTCCAGGGACTTGCATTGGCAC1297
Pro205SerATTTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGG
CCT to TCTGGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCT
AGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCATG1298
AGGAGTGCCACTTGCAAAGGAGCGATCCACACGAAATGTGC
CAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAAAACA
GGATCGCTCCTTTGCAA1299
TTGCAAAGGAGCGATCC1300
|
Cystic fibrosisTTTGCTGTGCTTTTATTTTCCAGGGACTTGCATTGGCACATTT1301
Leu206TrpCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGGGGC
TTG to TGGTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGG
CCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCC1302
CATGAGGAGTGCCACTTGCAAAGGAGCGATCCACACGAAAT
GTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAA
CGCTCCTTTGCAAGTGG1303
CCACTTGCAAAGGAGCG1304
|
Cystic fibrosisTTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGGG1305
Gln220TermGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGGACT
CAG to TAGTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGGC
GCCCAGCCTGAAAAAGGGCAAGGACTATCAGGAAACCAAGT1306
CCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCC
CATGAGGAGTGCCACTTGCAAAGGAGCGATCCACACGAA
AGTTGTTACAGGCGTCT1307
AGACGCCTGTAACAACT1308
|
Cystic fibrosisCCTTTGCAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTT1309
Cys225ArgGTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT
TGT-CGTCCTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGA
TCATCATTCTCCCTAGCCCAGCCTGAAAAAGGGCAAGGACTA1310
TCAGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAACAAC
TCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAGG
CTGCCTTCTGTGGACTT1311
AAGTCCACAGAAGGCAG1312
|
Cystic fibrosisTGGGGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGT1313
Val232AspGGACTTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGG
GTG to GACCTAGGGAGAATGATGATGAAGTACAGGTAGCAACCTAT
ATAGGTTGCTACCTGTACTTCATCATCATTCTCCCTAGCCCA1314
GCCTGAAAAAGGGCAAGGACTATCAGGAAACCAAGTCCACA
GAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCA
CCTGATAGTCCTTGCCC1315
GGGCAAGGACTATCAGG1316
|
Cystic fibrosisGTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT1317
Gly239ArgCCTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGATGAA
GGG to AGGGTACAGGTAGCAACCTATTTTCATAACTTGAAAGTTT
AAACTTTCAAGTTATGAAAATAGGTTGCTACCTGTACTTCATC1318
ATCATTCTCCCTAGCCCAGCCTGAAAAAGGGCAAGGACTATC
AGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAAC
TTTCAGGCTGGGCTAGG1319
CCTAGCCCAGCCTGAAA1320
|
EXAMPLE 10
[0132] Cyclin-dependent kinase inhibitor 2A-CDKN2A
[0133] The human CDKN2A gene was also designated MTS-1 for multiple tumor suppressor-1 and has been implicated in multiple cancers including, for example, malignant melanoma. Malignant melanoma is a cutaneous neoplasm of melanocytes. Melanomas generally have features of asymmetry, irregular border, variegated color, and diameter greater than 6 mm. The precise cause of melanoma is unknown, but sunlight and heredity are risk factors. Melanoma has been increasing during the past few decades.
[0134] The CDKN2A gene has been found to be homozygously deleted at high frequency in cell lines derived from tumors of lung, breast, brain, bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell lines carried at least one copy of CDKN2A in combination with a deleted allele. Melanoma cell lines that carried at least 1 copy of CDKN2A frequently showed nonsense, missense, or frameshift mutations in the gene. Thus, CDKN2A may rival p53 (see Example 5) in the universality of its involvement in tumorigenesis. The attached table discloses the correcting oligonucleotide base sequences for the CDKN2A oligonucleotides of the invention.
18TABLE 17
|
|
CDKN2A Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO
|
MelanomaGGGCGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAG1321
Trp15TermCATGGAGCCTTCGGCTGACTGGCTGGCCACGGCCGCGGCCC
TGG-TAGGGGGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGG
CCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACCCCG1322
GGCCGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCCATGC
TGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCGCCC
GGCTGACTGGCTGGCCA1323
TGGCCAGCCAGTCAGCC1324
|
MelanomaCGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAGCAT1325
Leu16ProGGAGCCTTCGGCTGACTGGCTGGCCACGGCCGCGGCCCGG
CTG-CCGGGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGC
GCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACC1326
CCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCC
ATGCTGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCG
TGACTGGCTGGCCACGG1327
CCGIGGCCAGCCAGTCA1328
|
MelanomaCGGCGGCGGGGAGCAGCATGGAGCCTTCGGCTGACTGGCTG1329
Gly23AspGCCACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGTGCGGG
GGT-GATCGCTGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAG
CTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGCGC1330
CCGCACCTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCA
GCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCGCCG
GGCCCGGGGTCGGGTAG1331
CTACCCGACCCCGGGCC1332
|
MelanomaCGGCGGGGAGCAGCATGGAGCCTTCGGCTGACTGGCTGGCC1333
Arg24ProACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGTGCGGGCGC
CGG-CCGTGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAGTTA
TAACTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGC1334
GCCCGCACCTCCTCTACCCGACCCCGGGCCGCGGCCGTGGC
CAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCG
CCGGGGTCGGGTAGAGG1335
CCTCTACCCGACCCCGG1336
|
MelanomaCGGCTGACTGGCTGGCCACGGCCGCGGCCCGGGGTCGGGT1337
Leu32ProAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGCGCTGCCC
CTG-CCGAACGCACCGAATAGTTACGGTCGGAGGCCGATCCAGGTGGG
CCCACCTGGATCGGCCTCCGACCGTAACTATTCGGTGCGTTG1338
GGCAGCGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTAC
CCGACCCCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCG
GGCGCTGCTGGAGGCGG1339
CCGCCTCCAGCAGCGCC1340
|
MelanomaGGCTGGCCACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGT1341
Gly35AlaGCGGGCGCTGCTGGAGGCGGGGGCGCTGCCCAACGCACCG
GGG-GCGAATAGTTACGGTCGGAGGCCGATCCAGGTGGGTAGAGGGTC
GACCCTCTACCCACCTGGATCGGCCTCCGACCGTAACTATTC1342
GGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGCGCCCGCAC
CTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCAGCC
GGAGGCGGGGGCGCTGC1343
GCAGCGCCCCCGCCTCC1344
|
MelanomaGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGCGCTG1345
Tyr44TermCCCAACGCACCGAATAGTTACGGTCGGAGGCCGATCCAGGTG
TACg-TAAGGTAGAGGGTCTGCAGCGGGAGCAGGGGATGGCGGGCGA
TCGCCCGCCATCCCCTGCTCCCGCTGCAGACCCTCTACCCAC1346
CTGGATCGGCCTCCGACCGTAACTATTCGGTGCGTTGGGCAG
CGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACC
AATAGTTACGGTCGGAG1347
CTCCGACCGTAACTATT1348
|
MelanomaTCTCCCATACCTGCCCCCACCCTGGCTCTGACCACTCTGCTC1349
Met53IleTCTCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGG
ATGa-ATCAGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCA
TGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCG1350
CCACGCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAG
CAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGGAGA
GTCATGATGATGGGCAG1351
CTGCCCATCATCATGAC1352
|
MelanomaCCCATACCTGCCCCCACCCTGGCTCTGACCACTCTGCTCTCT1353
Met54IleCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGGAGC
ATGg-ATTTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCAGAC
GTCTGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT1354
CCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGAGA
GAGCAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGG
ATGATGATGGGCAGCGC1355
GCGCTGCCCATCATCAT1356
|
MelanomaGCCGGCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGC1357
Ser56IleAGGTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTG
AGC-ATCCTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGC
GCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCA1358
GCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGACCTGCC
AGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGGCCGGC
GATGGGCAGCGCCCGAG1359
CTCGGGCGCTGCCCATC1360
|
MelanomaGGCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGG1361
Ala57ValTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTG
GCC-GTCCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCAC
GTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCA1362
GCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGACCT
GCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGGCC
GGGCAGCGCCCGAGTGG1363
CCACTCGGGCGCTGCCC1364
|
MelanomaCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTC1365
Arg58TermATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGCT
cCGA-TGACCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTC
GAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG1366
CAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGAC
CTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGG
GCAGCGCCCGAGTGGCG1367
CGCCACTCGGGCGCTGC1368
|
MelanomaCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTCATGAT1369
Val59GlyGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGCTCCACG
GTG-GGGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCAC
GTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTG1370
GAGCAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCA
TGACCTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTG
CGCCCGAGTGGCGGAGC1371
GCTCCGCCACTCGGGCG1372
|
MelanomaTCTGACCACTCTGCTCTCTCTGGCAGGTCATGATGATGGGCA1373
Leu62ProGCGCCCGCGTGGCGGAGCTGCTGCTGCTCCACGGCGCGGA
CTG-CCGGCCCAACTGCGCAGACCCTGCCACTCTCACCCGACCGGT
ACCGGTCGGGTGAGAGTGGCAGGGTCTGCGCAGTTGGGCTC1374
CGCGCCGTGGAGCAGCAGCAGCTCCGCCACGCGGGCGCTG
CCCATCATCATGACCTGCCAGAGAGAGCAGAGTGGTCAGA
GGCGGAGCTGCTGCTGC1375
GCAGCAGCAGCTCCGCC1376
|
MelanomaTCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGGAG1377
Ala68ValCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCAGACCC
GCG-GTGTGCCACTCTCACCCGACCGGTGCATGATGCTGCCCGGGA
TCCCGGGCAGCATCATGCACCGGTCGGGTGAGAGTGGCAGG1378
GTCTGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT
CCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGA
GCACGGCGCGGAGCCCA1379
TGGGCTCCGCGCCGTGG1380
|
MelanomaCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGC1381
Asn71LysTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTC
AACt-AAAACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTG
CAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGA1382
GAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG
CAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATG
GAGCCCAACTGCGCCGA1383
TCGGCGCAGTTGGGCTC1384
|
MelanomaTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTG1385
Asn71SerCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCT
AAC-AGCCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCT
AGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAG1386
AGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCA
GCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGA
GGAGCCCAACTGCGCCG1387
CGGCGCAGTTGGGCTCC1388
|
MelanomaAGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCCGAC1389
Pro81LeuCCCGCCACTCTCACCCGACCCGTGCACGACGCTGCCCGGGA
CCC-CTCGGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGCCGG
CCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTC1390
CCGCGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGG
TCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT
CACCCGACCCGTGCACG1391
CGTGCACGGGTCGGGTG1392
|
MelanomaCTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCAC1393
Asp84TyrTCTCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCC
cGAC-TACTGGACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGC
GCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGG1394
AAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGT
GGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAG
CCGTGCACGACGCTGCC1395
GGCAGCGTCGTGCACGG1396
|
MelanomaCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCT1397
Ala85ThrCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGG
cGCT-ACTACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGG
CCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCC1398
AGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAG
AGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG
TGCACGACGCTGCCCGG1399
CCGGGCAGCGTCGTGCA1400
|
MelanomaGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCGA1401
Arg87ProCCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGGACACGCT
CGG-CCGGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCG
CGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAG1402
CGTGTCCAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTC
GGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGC
CGCTGCCCGGGAGGGCT1403
AGCCCTCCCGGGCAGCG1404
|
MelanomaGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCG1405
Arg87TrpACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGGACACGC
cCGG-TGGTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGC
GCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGC1406
GTGTCCAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCG
GGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCC
ACGCTGCCCGGGAGGGC1407
GCCCTCCCGGGCAGCGT1408
|
MelanomaCTCTCACCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTC1409
Leu97ArgCTGGACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCT
CTG-CGGGGACGTGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTT
AAGTCCACGGGCAGACGACCCCAGGCATCGCGCACGTCCAG1410
CCGCGCCCCGGCCCGGTCCAGCACCACCAGCGTGTCCAGGA
AGCCCTCCCGGGCAGCATCATGCACCGGTCGGGTGAGAG
GGTGGTGCTGCACCGGG1411
CCCGGTGCAGCACCACC1412
|
MelanomaCCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGAC1413
Arg99ProACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACG
CGG-CCGTGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGA
TCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCGCGCAC1414
GTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGT
CCAGGAAGCCCTCCCGGGCAGCATCATGCACCGGTCGGG
GCTGCACCGGGCCGGGG1415
CCCCGGCCCGGTGCAGC1416
|
MelanomaCCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGACACGCT1417
Gly101TrpGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCGC
cGGG-TGGGATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGAGGAGC
GCTCCTCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCG1418
CGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAG
CGTGTCCAGGAAGCCCTCCCGGGCAGCATCATGCACCGG
ACCGGGCCGGGGCGCGG1419
CCGCGCCCCGGCCCGGT1420
|
MelanomaCGGGAGGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGC1421
Arg107CysCGGGGCGCGGCTGGACGTGCGCGATGCCTGGGGTCGTCTGC
gCGC-TGCCCGTGGACTTGGCCGAGGAGCGGGGCCACCGCGACGTTG
CAACGTCGCGGTGGCCCCGCTCCTCGGCCAAGTCCACGGGC1422
AGACGACCCCAGGCATCGCGCACGTCCAGCCGCGCCCCGGC
CCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCG
TGGACGTGCGCGATGCC1423
GGCATCGCGCACGTCCA1424
|
MelanomaCACCGGGCCGGGGCGCGGCTGGACGTGCGCGATGCCTGGG1425
Ala118ThrGCCGTCTGCCCGTGGACCTGGCTGAGGAGCTGGGCCATCGC
gGCT-ACTGATGTCGCACGGTACCTGCGCGCGGCTGCGGGGGGCACCA
TGGTGCCCCCCGCAGCCGCGCGCAGGTACCGTGCGACATCG1426
CGATGGCCCAGCTCCTCAGCCAGGTCCACGGGCAGACGGCC
CCAGGCATCGCGCACGTCCAGCCGCGCCCCGGCCCGGTG
TGGACCTGGCTGAGGAG1427
CTCCTCAGCCAGGTCCA1428
|
MelanomaTGCGCGATGCCTGGGGCCGTCTGCCCGTGGACCTGGCTGAG1429
Val126AspGAGCTGGGCCATCGCGATGTCGCACGGTACCTGCGCGCGGC
GTC-GACTGCGGGGGGCACCAGAGGCAGTAACCATGCCCGCATAGA
TCTATGCGGGCATGGTTACTGCCTCTGGTGCCCCCCGCAGCC1430
GCGCGCAGGTACCGTGCGACATCGCGATGGCCCACCTCCTC
AGCCAGGTCCACGGGCAGACGGCCCCAGGCATCGCGCA
TCGCGATGTCGCACGGT1431
ACCGTGCGACATCGCGA1432
|
Adenomatous Polyposis of the Colon—APC
[0135] Adenomatous polyposis of the colon is characterized by adenomatous polyps of the colon and rectum; in extreme cases the bowel is carpeted with a myriad of polyps. This is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years.
[0136] Mutations in the APC gene are an initiating event for both familial and sporadic colorectal tumorigenesis and many alleles of the APC gene have been identified. Carcinoma may arise at any age from late childhood through the seventh decade with presenting features including, for example, weight loss and inanition, bowel obstruction, or bloody diarrhea. Cases of new mutation still present in these ways but in areas with well organized registers most other gene carriers are detected. The attached table discloses the correcting oligonucleotide base sequences for the APC oligonucleotides of the invention.
19TABLE 18
|
|
APC Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Adenomatous polyposisGGATCTGTATCAAGCCGTTCTGGAGAGTGCAGTCCTGTTCCT1433
coliATGGGTTCATTTCCAAGAAGAGGGTTTGTAAATGGAAGCAGA
Arg121TermGAAAGTACTGGATATTTAGAAGAACTTGAGAAAGAGA
AGA-TGATCTCTTTCTCAAGTTCTTCTAAATATCCAGTACTTTCTCTGCTT1434
CCATTTACAAACCCTCTTCTTGGAAATGAACCCATAGGAACAG
GACTGCACTCTCCAGAACGGCTTGATACAGATCC
TTCCAAGAAGAGGGTTT1435
AAACCCTCTTCTTGGAA1436
Adenomatous polyposisAAAAAAAAAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAA1437
coliGAAAAGGAAAAAGACTGGTATTACGCTCAACTTCAGAATCTCA
Trp157TermCTAAAAGAATAGATAGTCTTCCTTTAACTGAAAA
TGG-TAGTTTTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGAGATTCTG1438
AAGTTGAGCGTAATACCAGTCTTTTTCCTTTTCTTCTTTGTCAA
GATCAGCAAGAAGCAATGACCTATTTTTTTTTT
AAAAGACTGGTATTACG1439
CGTAATACCAGTCTTTT1440
Adenomatous polyposisAAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAAGAAAAG 1441
coliGAAAAAGACTGGTATTACGCTCAACTTCAGAATCTCACTAAAA
Tyr159TermGAATAGATAGTCTTCCTTTAACTGAAAATGTAAGT
TAC-TAGACTTACATTTTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGA1442
GATTCTGAAGTTGAGCGTAATACCAGTCTTTTTCCTTTTCTTCT
TTGTCAAGATCAGCAAGAAGCAATGACCTATTT
TGGTATTACGCTCAACT1443
AGTTGAGCGTAATACCA1444
Adenomatous polyposisTTGCTTCTTGCTGATCTTGACAAAGAAGAAAAGGAAAAAGACT1445
coilGGTATTACGCTCAACTTCAGAATCTCACTAAAAGAATAGATAG
Gln163TermTCTTCCTTTAACTGAAAATGTAAGTAACTGGCAGT
CAG-TAGACTGCCAGTTACTTACATTTTCAGTTAAAGGAAGACTATCTATT1446
CTTTTAGTGAGATTCTGAAGTTGAGCGTAATACCAGTCTTTTTC
CTTTTCTTCTTTGTCAAGATCAGCAAGAAGCAA
CTCAACTTCAGAATCTC1447
GAGATTCTGAAGTTGAG1448
Adenomatous polyposisCTTGACAAAGAAGAAAAGGAAAAAGACTGGTATTACGCTCAAC1449
coliTTCAGAATCTCACTAAAAGAATAGATAGTCTTCCTTTAACTGAA
Arg168TermAATGTAAGTAACTGGCAGTACAACTTATTTGAAA
AGA-TGATTTCAAATAAGTTGTACTGCCAGTTACTTACATTTTCAGTTAAA1450
GGAAGACTATCTATTCTTTTAGTGAGATTCTGAAGTTGAGCGT
AATACCAGTCTTTTTCCTTTTCTTCTTTGTCAAG
TCACTAAAAGAATAGAT1451
ATCTATTCTTTTAGTGA1452
Adenomatous polyposisAAGAAAAGGAAAAAGACTGGTATTACGCTCAACTTCAGAATCT1453
coliCACTAAAAGAATAGATAGTCTTCCTTTAACTGAAAATGTAAGTA
Ser171lleACTGGCAGTACAACTTATTTGAAACTTTAATAAC
AGT-ATTGTTATTAAAGTTTCAAATAAGTTGTACTGCCAGTTACTTACATT1454
TTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGAGATTCTGAA
GTTGAGCGTAATACCAGTCTTTTTCCTTTTCTT
AATAGATAGTCTTCCTT1455
AAGGAAGACTATCTATT1456
Adenomatous polyposisGATTAACGTAAATACAAGATATTGATACTTTTTTATTATTTGTGG1457
coliTTTAGTTTTCCTTACAAACAGATATGACCAGAAGGCAATTGG
Gln181TermAATATGAAGCAAGGCAAATCAGAGTTGCGATGG
CAA-TAACCATCGCAACTCTGATTTGCCTTGCTTCATATTCCAATTGCCT1458
TCTGGTCATATCTGTTTGTAAGGAAAACTAAAACCACAAATAAT
AAAAAAGTATCAATATCTTGTATTTACGTTAATC
TTTCCTTACAAACAGAT1459
ATCTGTTTGTAAGGAAA1460
Adenomatous polyposisCTTTTTTATTATTTGTGGTTTTAGTTTTCCTTACAAACAGATATG1461
coliACCAGAAGGCAATTGGAATATGAAGCAAGGCAAATCAGAGTT
Glu19OTermGCGATGGAAGAACAACTAGGTACCTGCCAGGATA
GAA-TAATATCCTGGCAGGTACCTAGTTGTTCTTCCATCGCAACTCTGAT1462
TTGCCTTGCTTCATATTCCAATTGCCTTCTGGTCATATCTGTTT
GTAAGGAAAACTAAAACCACAAATAATAAAAAAG
GGCAATTGGAATATGAA1463
TTCATATTCCAATTGCC1464
Adenomatous polyposisCAATTGGAATATGAAGCAAGGCAAATCAGAGTTGCGATGGAA1465
coliGAACAACTAGGTACCTGCCAGGATATGGAAAAACGAGCACAG
Gln2O8TermGTAAGTTACTTGTTTCTAAGTGATAAAACAGCGAAGA
CAG-TAGTCTTCGCTGTTTTATCACTTAGAAACAAGTAACTTACCTGTGCT1466
CGTTTTTCCATATCCTGGCAGGTACCTAGTTGTTCTTCCATCG
CAACTCTGATTTGCCTTGCTTCATATTCCAATTG
GTACCTGCCAGGATATG1467
CATATCCTGGCAGGTAC1468
Adenomatous polyposisGCAAGGCAAATCAGAGTTGCGATGGAAGAACAACTAGGTACC1469
coilTGCCAGGATATGGAAAAACGAGCACAGGTAAGTTACTTGTTTC
Arg213TermTAAGTGATAAAACAGCGAAGAGCTATTAGGAATAAA
CGA-TGATTTATTCCTAATAGCTCTTCGCTGTTTTATCACTTAGAAACAAG1470
TAACTTACCTGTGCTCGTTTTTCCATATCCTGGCAGGTACCTA
GTTGTTCTTCCATCGCAACTCTGATTTGCCTTGC
TGGAAAAACGAGCACAG1471
CTGTGCTCGTTTTTCCA1472
Adenomatous polyposisGTTTTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAA1473
coliAGGACATACTTCGTATACGACAGCTTTTACAGTCCCAAGCAAC
Arg232TermAGAAGCAGAGGTTAGTAAATTGCCTTTCTTGTTTG
CGA-TGACAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGCTTG1474
GGACTGTAAAAGCTGTCGTATACGAAGTATGTCCTTTTCGATT
TGCTGAATTCTGGCTATTCTTCGCTAAAATAAAAC
TTCGTATACGACAGCTT1475
AAGCTGTCGTATACGAA1476
Adenomatous polyposisTTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAAAGG1477
coliACATACTTCGTATACGACAGCTTTTACAGTCCCAAGCAACAGA
Gln233TermAGCAGAGGTTAGTAAATTGCCTTTCTTGTTTGTGG
CAG-TAGCCACAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGC1478
TTGGGACTGTAAAAGCTGTCGTATACGAAGTATGTCCTTTTCG
ATTTGCTGAATTCTGGCTATTCTTCGCTAAAATAA
GTATACGACAGCTTTTA1479
TAAAAGCTGTCGTATAC1480
Adenomatous polyposisAGAAAGCCTACACCATTTTTGCATGTACTGATGTTAACTCCAT1481
coliCTTAACAGAGGTCATCTCAGAACAAGCATGAAACCGGCTCAC
Gln247TermATGATGCTGAGCGGCAGAATGAAGGTCAAGGAGTGG
CAG-TAGCCACTCCTTGACCTTCATTCTGCCGCTCAGCATCATGTGAGC1482
CGGTTTCATGCTTGTTCTGAGATGACCTCTGTTAAGATGGAGT
TAACATCAGTACATGCAAAAATGGTGTAGGCTTTCT
GGTCATCTCAGAACAAG1483
CTTGTTCTGAGATGACC1484
Adenomatous polyposisCAGAACAAGCATGAAACCGGCTCACATGATGCTGAGCGGCAG1485
coliAATGAAGGTCAAGGAGTGGGAGAAATCAACATGGCAACTTCT
Gly267TermGGTAATGGTCAGGTAAATAAATTATTTTATCATATTT
GGA-TGAAAATATGATAAAATAATTTATTTACCTGACCATTACCAGAAGTT1486
GCCATGTTGATTTCTCCCACTCCTTGACCTTCATTCTGCCGCT
CAGCATCATGTGAGCCGGTTTCATGCTTGTTCTG
AAGGAGTGGGAGAAATC1487
GATTTCTCCCACTCCTT1488
Adenomatous polyposisCTTCAAATAACAAAGCATTATGGTTTATGTTGATTTTATTTTTCA1489
coliGTGCCAGCTCCTGTTGAACATCAGATCTGTCCTGCTGTGTGT
Glu443TermGTTCTAATGAAACTTTCATTTGATGAAGAGCATA
GAA-TAATATGCTCTTCATCAAATGAAAGTTTCATTAGAACACACACAGCA1490
GGACAGATCTGATGTTCAACAGGAGCTGGCACTGAAAAATAA
AATCAACATAAACCATAATGCTTTGTTATTTGAAG
CTCCTGTTGAACATCAG1491
CTGATGTTCAACAGGAG1492
Adenomatous polyposisCAGTGCCAGCTCCTGTTGAACATCAGATCTGTCCTGCTGTGT1493
coliGTGTTCTAATGAAACTTTCATTTGATGAAGAGCATAGACATGC
SER457TERAATGAATGAACTAGGTAAGACAAAAATGTTTTTTAA
TCA-TAATTAAAAAACATTTTTGTCTTACCTAGTTCATTCATTGCATGTCTA1494
TGCTCTTCATCAAATGAAAGTTTCATTAGAACACACACAGCAG
GACAGATCTGATGTTCAACAGGAGCTGGCACTG
GAAACTTTCATTTGATG1495
CATCAAATGAAAGTTTC1496
Adenomatous polyposisAGTTGTTTTATTTTAGATGATTGTCTTTTTCCTCTTGCCCTTTTT1497
coliAAATTAGGGGGACTACAGGCCATTGCAGAATTATTGCAAGTG
Gln473TermGACTGTGAAATGTACGGGCTTACTAATGACCACT
CAG-TAGAGTGGTCATTAGTAAGCCCGTACATTTCACAGTCCACTTGCAA1498
TAATTCTGCAATGGCCTGTAGTCCCCCTAATTTAAAAAGGGCA
AGAGGAAAAAGACAATCATCTAAAATAAAACAACT
GGGGACTACAGGCCATT1499
AATGGCCTGTAGTCCCC1500
Adenomatous polyposisTTTTAAATTAGGGGGACTACAGGCCATTGCAGAATTATTGCAA1501
coliGTGGACTGTGAAATGTACGGGCTTACTAATGACCACTACAGTA
Tyr486TermTTACACTAAGACGATATGCTGGAATGGCTTTGACA
TAC-TAGTGTCAAAGCCATTCCAGCATATCGTCTTAGTGTAATACTGTAG1502
TGGTCATTAGTAAGCCCGTACATTTCACAGTCCACTTGCAATA
ATTCTGCAATGGCCTGTAGTCCCCCTAATTTAAAA
GAAATGTACGGGCTTAC1503
GTAAGCCCGTACATTTC1504
Adenomatous polyposisTTGCAAGTGGACTGTGAAATGTATGGGCTTACTAATGACCACT1505
coliACAGTATTACACTAAGACGATATGCTGGAATGGCTTTGACAAA
Arg499TermCTTGACTTTTGGAGATGTAGCCAACAAGGTATGTT
CGA-TGAAACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTGTCAA1506
AGCCATTCCAGCATATCGTCTTAGTGTAATACTGTAGTGGTCA
TTAGTAAGCCCATACATTTCACAGTCCACTTGCAA
CACTAAGACGATATGCT1507
AGCATATCGTCTTAGTG1508
Adenomatous polyposisAGTGGACTGTGAAATGTATGGGCTTACTAATGACCACTACAGT1509
coliATTACACTAAGACGATATGCTGGAATGGCTTTGACAAACTTGA
Tyr5OOTermCTTTTGGAGATGTAGCCAACAAGGTATGTTTTTAT
TAT-TAGATAAAAACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTG1510
TCAAAGCCATTCCAGCATATCGTCTTAGTGTAATACTGTAGTG
GTCATTAGTAAGCCCATACATTTCACAGTCCACT
AGACGATATGCTGGAAT1511
ATTCCAGCATATCGTCT1512
Adenomatous polyposisGACAAATTCCAACTCTAATTAGATGACCCATATTCTGTTTCTTA1513
coliCTAGGAATCAACCCTCAAAAGCGTATTGAGTGCCTTATGGAAT
Lys586TermTTGTCAGCACATTGCACTGAGAATAAAGCTGATA
AAA-TAATATCAGCTTTATTCTCAGTGCAATGTGCTGACAAATTCCATAA1514
GGCACTCAATACGCTTTTGAGGGTTGATTCCTAGTAAGAAACA
GAATATGGGTCATCTAATTAGAGTTGGAATTTGTC
CAACCCTCAAAAGCGTA1515
TACGCTTTTGAGGGTTG1516
Adenomatous polyposisTAGATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAA1517
coliAGCGTATTGAGTGCCTTATGGAATTTGTCAGCACATTGCACTG
Leu592TermAGAATAAAGCTGATATATGTGCTGTAGATGGTGC
TTA-TGAGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGCAAT1518
GTGCTGACAAATTCCATAAGGCACTCAATACGCTTTTGAGGGT
TGATTCCTAGTAAGAAACAGAATATGGGTCATCTA
GAGTGCCTTATGGAATT1519
AATTCCATAAGGCACTC1520
Adenomatous polyposisATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAG1521
coliCGTATTGAGTGCCTTATGGAATTTGTCAGCACATTGCACTGAG
Trp593TermAATAAAGCTGATATATGTGCTGTAGATGGTGCACT
TGG-TAGAGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGC1522
AATGTGCTGACAAATTCCATAAGGCACTCAATACGCTTTTGAG
GGTTGATTCCTAGTAAGAAACAGAATATGGGTCAT
TGCCTTATGGAATTTGT1523
ACAAATTCCATAAGGCA1524
Adenomatous polyposisTGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAGC1525
coliGTATTGAGTGCCTTATGGAATTTGTCAGCACATTGCACTGAGA
Trp593TermATAAAGCTGATATATGTGCTGTAGATGGTGCACTT
TGG-TGAAAGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTG1526
CAATGTGCTGACAAATTCCATAAGGCACTCAATACGCTTTTGA
GGGTTGATTCCTAGTAAGAAACAGAATATGGGTCA
GCCTTATGGAATTTGTC1527
GACAAATTCCATAAGGC1528
Adenomatous polyposisTAAAGCTGATATATGTGCTGTAGATGGTGCACTTGCATTTTTG1529
coliGTTGGCACTCTTACTTACCGGAGCCAGACAAACACTTTAGCC
Tyr622TermATTATTGAAAGTGGAGGTGGGATATTACGGAATGTG
TAC-TAACACATTCCGTAATATCCCACCTCCACTTTCAATAATGGCTAAA1530
GTGTTTGTCTGGCTCCGGTAAGTAAGAGTGCCAACCAAAAAT
GCAAGTGCACCATCTACAGCACATATATCAGCTTTA
CTTACTTACCGGAGCCA1531
TGGCTCCGGTAAGTAAG1532
Adenomatous polyposisGATATATGTGCTGTAGATGGTGCACTTGCATTTTTGGTTGGCA1533
coliCTCTTACTTACCGGAGCCAGACAAACACTTTAGCCATTATTGA
Gln625TermAAGTGGAGGTGGGATATTACGGAATGTGTCCAGCT
CAG-TAGAGCTGGACACATTCCGTAATATCCCACCTCCACTTTCAATAAT1534
GGCTAAAGTGTTTGTCTGGCTCCGGTAAGTAAGAGTGCCAAC
CAAAAATGCAAGTGCACCATCTACAGCACATATATC
ACCGGAGCCAGACAAAC1535
GTTTGTCTGGCTCCGGT1536
Adenomatous polyposisTAGATGGTGCACTTGCATTTTTGGTTGGCACTCTTACTTACCG1537
coliGAGCCAGACAAACACTTTAGCCATTATTGAAAGTGGAGGTGG
Leu629TermGATATTACGGAATGTGTCCAGCTTGATAGCTACAAA
TTA-TAATTTGTAGCTATCAAGCTGGACACATTCCGTAATATCCCACCTC1538
CACTTTCAATAATGGCTAAAGTGTTTGTCTGGCTCCGGTAAGT
AAGAGTGCCAACCAAAAATGCAAGTGCACCATCTA
AAACACTTTAGCCATTA1539
TAATGGCTAAAGTGTTT1540
Adenomatous polyposisGCCATTATTGAAAGTGGAGGTGGGATATTACGGAATGTGTCC1541
coliAGCTTGATAGCTACAAATGAGGACCACAGGTATATATAGAGTT
Glu65OTermTTATATTACTTTTAAAGTACAGAATTCATACTCTCA
GAG-TAGTGAGAGTATGAATTCTGTACTTTAAAAGTAATATAAAACTCTAT1542
ATATACCTGTGGTCCTCATTTGTAGCTATCAAGCTGGACACAT
TCCGTAATATCCCACCTCCACTTTCAATAATGGC
CTACAAATGAGGACCAC1543
GTGGTCCTCATTTGTAG1544
Adenomatous polyposisTGCATGTGGAACTTTGTGGAATCTCTCAGCAAGAAATCCTAAA1545
coliGACCAGGAAGCATTATGGGACATGGGGGCAGTTAGCATGCTC
Trp699TermAAGAACCTCATTCATTCAAAGCACAAAATGATTGCT
TGG-TGAAGCAATCATTTTGTGCTTTGAATGAATGAGGTTCTTGAGCATG1546
CTAACTGCCCCCATGTCCCATAATGCTTCCTGGTCTTTAGGAT
TTCTTGCTGAGAGATTCCACAAAGTTCCACATGCA
GCATTATGGGACATGGG1547
CCCATGTCCCATAATGC1548
Adenomatous polyposisAAGACCAGGAAGCATTATGGGACATGGGGGCAGTTAGCATGC1549
coliTCAAGAACCTCATTCATTCAAAGCACAAAATGATTGCTATGGG
Ser713TermAAGTGCTGCAGCTTTAAGGAATCTCATGGCAAATAG
TCA-TGACTATTTGCCATGAGATTCCTTAAAGCTGCAGCACTTCCCATAG1550
CAATCATTTTGTGCTTTGAATGAATGAGGTTCTTGAGCATGCT
AACTGCCCCCATGTCCCATAATGCTTCCTGGTCTT
CATTCATTCAAAGCACA1551
TGTGCTTTGAATGAATG1552
Adenomatous polyposisGGGGCAGTTAGCATGCTCAAGAACCTCATTCATTCAAAGCAC1553
coliAAAATGATTGCTATGGGAAGTGCTGCAGCTTTAAGGAATCTCA
Ser722GlyTGGCAAATAGGCCTGCGAAGTACAAGGATGCCAATA
AGT-GGTTATTGGCATCCTTGTACTTCGCAGGCCTATTTGCCATGAGATT1554
CCTTAAAGCTGCAGCACTTCCCATAGCAATCATTTTGTGCTTT
GAATGAATGAGGTTCTTGAGCATGCTAACTGCCCC
CTATGGGAAGTGCTGCA1555
TGCAGCACTTCCCATAG1556
Adenomatous polyposisTCTCCTGGCTCAGCTTGCCATCTCTTCATGTTAGGAAACAAAA1557
coliAGCCCTAGAAGCAGAATTAGATGCTCAGCACTTATCAGAAACT
Leu764TermTTTGACAATATAGACAATTTAAGTCCCAAGGCATC
TTA-TAAGATGCCTTGGGACTTAAATTGTCTATATTGTCAAAAGTTTCTGA1558
TAAGTGCTGAGCATCTAATTCTGCTTCTAGGGCTTTTTGTTTC
CTAACATGAAGAGATGGCAAGCTGAGCCAGGAGA
AGCAGAATTAGATGCTC1559
GAGCATCTAATTCTGCT1560
Adenomatous polyposisTTAGATGCTCAGCACTTATCAGAAACTTTTGACAATATAGACAA1561
coliTTTAAGTCCCAAGGCATCTCATCGTAGTAAGCAGAGACACAG
Ser784ThrCAAGTCTCTATGGTGATTATGTTTTTGACACCATC
TCT-ACTGATGGTGTCAAAAACATAATCACCATAGAGACTTGCTGTGTCT1562
CTGCTTACTACGATGAGATGCCTTGGGACTTAAATTGTCTATA
TTGTCAAAAGTTTCTGATAAGTGCTGAGCATCTAA
CCAAGGCATCTCATCGT1563
ACGATGAGATGCCTTGG1564
Adenomatous polyposisCTCATCGTAGTAAGCAGAGACACAGCAAGTCTCTATGGTGATT1565
coliATGTTTTTGACACCAATCGACATGATGATAATAGGTCAGACAT
Arg8O5TermTTTAATACTGGCACATGACTGTCCTTTCACCATAT
CGA-TGAATATGGTGAAAGGACAGTCATGTGCCAGTATTAAAATGTCTGA1566
CCTATTATCATCATGTCGATTGGTGTCAAAAACATAATCACCAT
AGAGACTTGCTGTGTCTCTGCTTACTACGATGAG
ACACCAATCGACATGAT1567
ATCATGTCGATTGGTGT1568
Adenomatous polyposisGGTCTAGGCAACTACCATCCAGCAACAGAAAATCCAGGAACT1569
coliTCTTCAAAGCGAGGTTTGCAGATCTCCACCACTGCAGCCCAG
Gln879TermATTGCCAAAGTCATGGAAGAAGTGTCAGCCATTCATA
CAG-TAGTATGAATGGCTGACACTTCTTCCATGACTTTGGCAATCTGGGC1570
TGCAGTGGTGGAGATCTGCAAACCTCGCTTTGAAGAAGTTCC
TGGATTTTCTGTTGCTGGATGGTAGTTGCCTAGACC
GAGGTTTGCAGATCTCC1571
GGAGATCTGCAAACCTC1572
Adenomatous polyposisTACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC1573
coliTGCTGCCCATACACATTCAAACACTTACAATTTCACTAAGTCG
Ser932TermGAAAATTCAAATAGGACATGTTCTATGCCTTATGC
TCA-TAAGCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG1574
TGAAATTGTAAGTGTTTGAATGTGTATGGGCAGCAGAGCTTCT
TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA
TACACATTCAAACACTT1575
AAGTGTTTGAATGTGTA1576
Adenomatous polyposisTACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC1577
coliTGCTGCCCATACACATTCAAACACTTACAATTTCACTAAGTCG
Ser932TermGAAAATTCAAATAGGACATGTTCTATGCCTTATGC
TCA-TGAGCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG1578
TGAAATTGTAAGTGTTTGAATGTGTATGGGCAGCAGAGCTTCT
TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA
TACACATTCAAACACTT1579
AAGTGTTTGAATGTGTA1580
Adenomatous polyposisGACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA1581
coliTACACATTCAAACACTTACAATTTCACTAAGTCGGAAAATTCAA
Tyr935TermATAGGACATGTTCTATGCCTTATGCCAAATTAGAA
TAC-TAGTTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT1582
CCGACTTAGTGAAATTGTAAGTGTTTGAATGTGTATGGGCAGC
AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC
AACACTTACAATTTCAC1583
GTGAAATTGTAAGTGTT1584
Adenomatous polyposisGACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA1585
coliTACACATTCAAACACTTACAATTTCACTAAGTCGGAAAATTCAA
Tyr935TermATAGGACATGTTCTATGCCTTATGCCAAATTAGAA
TAC-TAATTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT1586
CCGACTTAGTGAAATTGTAAGTGTTTGAATGTGTATGGGCAGC
AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC
AACACTTACAATTTCAC1587
GTGAAATTGTAAGTGTT1588
Adenomatous polyposisACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTAAGTTTT1589
coliGCAGTTATGGTCAATACCCAGCCGACCTAGCCCATAAAATACA
Tyr1000TermTAGTGCAAATCATATGGATGATAATGATGGAGAA
TAC-TAATTCTCCATCATTATCATCCATATGATTTGCACTATGTATTTTAT1590
GGGCTAGGTCGGCTGGGTATTGACCATAACTGCAAAACTTAC
TTTCATCATCTTCAGAATAGGATTCAATCGAGGGT
GGTCAATACCCAGCCGA1591
TCGGCTGGGTATTGACC1592
Adenomatous polyposisTACCCAGCCGACCTAGCCCATAAAATACATAGTGCAAATCATA1593
coliTGGATGATAATGATGGAGAACTAGATACACCAATAAATTATAG
Glu1020TermTCTTAAATATTCAGATGAGCAGTTGAACTCTGGAA
GAA-TAATTCCAGAGTTCAACTGCTCATCTGAATATTTAAGACTATAATTT1594
ATTGGTGTATCTAGTTCTCCATCATTATCATCCATATGATTTGC
ACTATGTATTTTATGGGCTAGGTCGGCTGGGTA
ATGATGGAGAACTAGAT1595
ATCTAGTTCTCCATCAT1596
Adenomatous polyposisATGAAACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTA1597
coliAGTTTTGCAGTTATGGTCAATACCCAGCCGACCTAGCCCATAA
Ser1032TermAATACATAGTGCAAATCATATGGATGATAATGATG
TCA-TAACATCATTATCATCCATATGATTTGCACTATGTATTTTATGGGCT1598
AGGTCGGCTGGGTATTGACCATAACTGCAAAACTTACTTTCAT
CATCTTCAGAATAGGATTCAATCGAGGGTTTCAT
GTTATGGTCAATACCCA1599
TGGGTATTGACCATAAC1600
Adenomatous polyposisTGAAGATGATGAAAGTAAGTTTTGCAGTTATGGTCAATACCCA1601
coliGCCGACCTAGCCCATAAAATACATAGTGCAAATCATATGGATG
Gln1041TermATAATGATGGAGAACTAGATACACCAATAAATTAT
CAA-TAAATAATTTATTGGTGTATCTAGTTCTCCATCATTATCATCCATAT1602
GATTTGCACTATGTATTTTATGGGCTAGGTCGGCTGGGTATTG
ACCATAACTGCAAAACTTACTTTCATCATCTTCA
GCCCATAAAATACATAG1603
CTATGTATTTTATGGGC1604
Adenomatous polyposisATAAATTATAGTCTTAAATATTCAGATGAGCAGTTGAACTCTGG1605
coliAAGGCAAAGTCCTTCACAGAATGAAAGATGGGCAAGACCCAA
Gln1O45TermACACATAATAGAAGATGAAATAAAACAAAGTGAGC
CAG-TAGGCTCACTTTGTTTTATTTCATCTTCTATTATGTGTTTGGGTCTT1606
GCCCATCTTTCATTCTGTGAAGGACTTTGCCTTCCAGAGTTCA
ACTGCTCATCTGAATATTTAAGACTATAATTTAT
GTCCTTCACAGAATGAA1607
TTCATTCTGTGAAGGAC1608
Adenomatous polyposisGAAAGATGGGCAAGACCCAAACACATAATAGAAGATGAAATAAA1609
coliAACAAAGTGAGCAAAGACAATCAAGGAATCAAAGTACAACTTA
Gln1O67TermTCCTGTTTATACTGAGAGCACTGATGATAAACACC
CAA-TAAGGTGTTTATCATCAGTGCTCTCAGTATAAACAGGATAAGTTGT1610
ACTTTGATTCCTTGATTGTCTTTGCTCACTTTGTTTTATTTCATC
TTCTATTATGTGTTTGGGTCTTGCCCATCTTTC
AGCAAAGACAATCAAGG1611
CCTTGATTGTCTTTGCT1612
Adenomatous polyposisAATAGAAGATGAAATAAAACAAAGTGAGCAAAGACAATCAAGG1613
coliAATCAAAGTACAACTTATCCTGTTTATACTGAGAGCACTGATG
Tyr1O75TermATAAACACCTCAAGTTCCAACCACATTTTGGACAG
TAT-TAGCTGTCCAAAATGTGGTTGGAACTTGAGGTGTTTATCATCAGTG1614
CTCTCAGTATAAACAGGATAAGTTGTACTTTGATTCCTTGATTG
TCTTTGCTCACTTTGTTTTATTTCATCTTCTATT
ACAACTTATCCTGTTTA1615
TAAACAGGATAAGTTGT1616
Adenomatous polyposisTGATGATAAACACCTCAAGTTCCAACCACATTTTGGACAGCAG1617
coliGAATGTGTTTCTCCATACAGGTCACGGGGAGCCAATGGTTCA
Tyri11O2TermGAAACAAATCGAGTGGGTTCTAATCATGGAATTAAT
TAC-TAGATTAATTCCATGATTAGAACCCACTCGATTTGTTTCTGAACCAT1618
TGGCTCCCCGTGACCTGTATGGAGAAACACATTCCTGCTGTC
CAAAATGTGGTTGGAACTTGAGGTGTTTATCATCA
TCTCCATACAGGTCACG1619
CGTGACCTGTATGGAGA1620
Adenomatous polyposisAACCACATTTTGGACAGCAGGAATGTGTTTCTCCATACAGGTC1621
coliACGGGGAGCCAATGGTTCAGAAACAAATCGAGTGGGTTCTAA
Ser111OTermTCATGGAATTAATCAAAATGTAAGCCAGTCTTTGTG
TCA-TGACACAAAGACTGGCTTACATTTTGATTAATTCCATGATTAGAACC1622
CACTCGATTTGTTTCTGAACCATTGGCTCCCCGTGACCTGTAT
GGAGAAACACATTCCTGCTGTCCAAAATGTGGTT
CAATGGTTCAGAAACAA1623
TTGTTTCTGAACCATTG1624
Adenomatous polyposisGGACAGCAGGAATGTGTTTCTCCATACAGGTCACGGGGAGCC1625
coliAATGGTTCAGAAACAAATCGAGTGGGTTCTAATCATGGAATTA
Arg1114TermATCAAAATGTAAGCCAGTCTTTGTGTCAAGAAGATG
CGA-TGACATCTTCTTGACACAAAGACTGGCTTACATTTTGATTAATTCCA1626
TGATTAGAACCCACTCGATTTGTTTCTGAACCATTGGCTCCCC
GTGACCTGTATGGAGAAACACATTCCTGCTGTCC
AAACAAATCGAGTGGGT1627
ACCCACTCGATTTGTTT1628
Adenomatous polyposisGGGTTCTAATCATGGAATTAATCAAAATGTAAGCCAGTCTTTG1629
coliTGTCAAGAAGATGACTATGAAGATGATAAGCCTACCAATTATA
Tyr1135TermGTGAACGTTACTCTGAAGAAGAACAGCATGAAGAA
TAT-TAGTTCTTCATGCTGTTCTTCTTCAGAGTAACGTTCACTATAATTGG1630
TAGGCTTATCATCTTCATAGTCATCTTCTTGACACAAAGACTG
GCTTACATTTTGATTAATTCCATGATTAGAACCC
GATGACTATGAAGATGA1631
TCATCTTCATAGTCATC1632
Adenomatous polyposisGAAGATGACTATGAAGATGATAAGCCTACCAATTATAGTGAAC1633
coliGTTACTCTGAAGAAGAACAGCATGAAGAAGAAGAGAGACCAA
Gln1152TermCAAATTATAGCATAAAATATAATGAAGAGAAACGTC
CAG-TAGGACGTTTCTCTTCATTATATTTTATGCTATAATTTGTTGGTCTCT1634
CTTCTTCTTCATGCTGTTCTTCTTCAGAGTAACGTTCACTATAA
TTGGTAGGCTTATCATCTTCATAGTCATCTTC
AAGAAGAACAGCATGAA1635
TTCATGCTGTTCTTCTT1636
Adenomatous polyposisGAAGAAGAGAGACCAACAAATTATAGCATAAAATATAATGAAG1637
coliAGAAACGTCATGTGGATCAGCCTATTGATTATAGTTTAAAATAT
Gln1175TermGCCACAGATATTCCTTCATCACAGAAACAGTCAT
CAG-TAGATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATTTTAAA1638
CTATAATCAATAGGCTGATCCACATGACGTTTCTCTTCATTATA
TTTTATGCTATAATTTGTTGGTCTCTCTTCTTC
ATGTGGATCAGCCTATT1639
AATAGGCTGATCCACAT1640
Adenomatous polyposisAAGAGAGACCAACAAATTATAGCATAAAATATAATGAAGAGAA1641
coliACGTCATGTGGATCAGCCTATTGATTATAGTTTAAAATATGCCA
Pro1176LeuCAGATATTCCTTCATCACAGAAACAGTCATTTTC
CCT-CTTGAAAATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATT1642
TTAAACTATAATCAATAGGCTGATCCACATGACGTTTCTCTTCA
TTATATTTTATGCTATAATTTGTTGGTCTCTCTT
GGATCAGCCTATTGATT1643
AATCAATAGGCTGATCC1644
Adenomatous polyposisATAAAATATAATGAAGAGAAACGTCATGTGGATCAGCCTATTG1645
coliATTATAGTTTAAAATATGCCACAGATATTCCTTCATCACAGAAA
Ala1184ProCAGTCATTTTCATTCTCAAAGAGTTCATCTGGAC
GCC-CCCGTCCAGATGAACTCTTTGAGAATGAAAATGACTGTTTCTGTGA1646
TGAAGGAATATCTGTGGCATATTTTAAACTATAATCAATAGGCT
GATCCACATGACGTTTCTCTTCATTATATTTTAT
TAAAATATGCCACAGAT1647
ATCTGTGGCATATTTTA1648
Adenomatous polyposisATCAGCCTATTGATTATAGTTTAAAATATGCCACAGATATTCCT1649
coliTCATCACAGAAACAGTCATTTTCATTCTCAAAGAGTTCATCTG
Ser1194TermGACAAAGCAGTAAAACCGAACATATGTCTTCAAG
TCA-TGACTTGAAGACATATGTTCGGTTTTACTGCTTTGTCCAGATGAAC1650
TCTTTGAGAATGAAAATGACTGTTTCTGTGATGAAGGAATATCT
GTGGCATATTTTAAACTATAATCAATAGGCTGAT
GAAACAGTCATTTTCAT1651
ATGAAAATGACTGTTTC1652
Adenomatous polyposisATTATAGTTTAAAATATGCCACAGATATTCCTTCATCACAGAAA1653
coliCAGTCATTTTCATTCTCAAAGAGTTCATCTGGACAAAGCAGTA
Ser1198TermAAACCGAACATATGTCTTCAAGCAGTGAGAATAC
TCA-TGAGTATTCTCACTGCTTGAAGACATATGTTCGGTTTTACTGCTTTG1654
TCCAGATGAACTCTTTGAGAATGAAAATGACTGTTTCTGTGAT
GAAGGAATATCTGTGGCATATTTTAAACTATAAT
TTCATTCTCAAAGAGTT1655
AACTCTTTGAGAATGAA1656
Adenomatous polyposisACCGAACATATGTCTTCAAGCAGTGAGAATACGTCCACACCTT1657
coliCATCTAATGCCAAGAGGCAGAATCAGCTCCATCCAGTTCTGC
Gln1228TermACAGAGTAGAAGTGGTCAGCCTCAAAGGCTGCCACT
CAG-TAGAGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGTGCAGAA1658
CTGGATGGAGCTGATTCTGCCTCTTGGCATTAGATGAAGGTG
TGGACGTATTCTCACTGCTTGAAGACATATGTTCGGT
CCAAGAGGCAGAATCAG1659
CTGATTCTGCCTCTTGG1660
Adenomatous polyposisCATATGTCTTCAAGCAGTGAGAATACGTCCACACCTTCATCTA1661
coliATGCCAAGAGGCAGAATCAGCTCCATCCAGTTCTGCACAGAG
Gln1230TermTAGAAGTGGTCAGCCTCAAAGGCTGCCACTTGCAAG
CAG-TAGCTTGCAAGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGT1662
GCAGAACTGGATGGAGCTGATTCTGCCTCTTGGCATTAGATG
AAGGTGTGGACGTATTCTCACTGCTTGAAGACATATG
GGCAGAATCAGCTCCAT1663
ATGGAGCTGATTCTGCC1664
Adenomatous polyposisTCAGCTCCATCCAAGTTCTGCACAGAGTAGAAGTGGTCAGCC1665
coliTCAAAAGGCTGCCACTTGCAAAGTTTCTTCTATTAACCAAGAA
Cys1249TermACAATACAGACTTATTGTGTAGAAGATACTCCAATA
TGC-TGATATTGGAGTATCTTCTACACAATAAGTCTGTATTGTTTCTTGGT1666
TAATAGAAGAAACTTTGCAAGTGGCAGCCTTTTGAGGCTGACC
ACTTCTACTCTGTGCAGAACTTGGATGGAGCTGA
GCCACTTGCAAAGTTTC1667
GAAACTTTGCAAGTGGC1668
Adenomatous polyposisAGTTTCTTCTATTAACCAAGAAACAATACAGACTTATTGTGTAG1669
coliAAGATACTCCAATATGTTTTTCAAGATGTAGTTCATTATCATCT
Cys1270TermTTGTCATCAGCTGAAGATGAAATAGGATGTAAT
TGT-TGAATTACATCCTATTTCATCTTCAGCTGATGACAAAGATGATAATG1670
AACTACATCTTGAAAAACATATTGGAGTATCTTCTACACAATAA
GTCTGTATTGTTTCTTGGTTAATAGAAGAAACT
CCAATATGTTTTTCAAG1671
CTTGAAAAACATATTGG1672
Adenomatous polyposisAAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATATGT1673
coliTTTTCAAGATGTAGTTCATTATCATCTTTGTCATCAGCTGAAGA
Ser1276TermTGAAATAGGATGTAATCAGACGACACAGGAAGC
TCA-TGAGCTTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTG1674
ATGACAAAGATGATAATGAACTACATCTTGAAAAACATATTGGA
GTATCTTCTACACAATAAGTCTGTATTGTTTCTT
ATGTAGTTCATTATCAT1675
ATGATAATGAACTACAT1676
Adenomatous polyposisGATACTCCAATATGTTTTTCAAGATGTAGTTCATTATCATCTTT1677
coliGTCATCAGCTGAAGATGAAATAGGATGTAATCAGACGACACA
Glu1286TermGGAAGCAGATTCTGCTAATACCCTGCAAATAGCAG
GAA-TAACTGCTATTTGCAGGGTATTAGCAGAATCTGCTTCCTGTGTCGT1678
CTGATTACATCCTATTTCATCTTCAGCTGATGACAAAGATGATA
ATGAACTACATCTTGAAAAACATATTGGAGTATC
CTGAAGATGAAATAGGA1679
TCCTATTTCATCTTCAG1680
Adenomatous polyposisTGTAGTTCATTATCATCTTTGTCATCAGCTGAAGATGAAATAGG1681
coliATGTAATCAGACGACACAGGAAGCAGATTCTGCTAATACCCTG
Gln1294TermCAAATAGCAGAAATAAAAGAAAAGATTGGAACTA
CAG-TAGTAGTTCCAATCTTTTCTTTTATTTCTGCTATTTGCAGGGTATTA1682
GCAGAATCTGCTTCCTGTGTCGTCTGATTACATCCTATTTCAT
CTTCAGCTGATGACAAAGATGATAATGAACTACA
AGACGACACAGGAAGCA1683
TGCTTCCTGTGTCGTCT1684
Predisposition to,TAGGATGTAATCAGACGACACAGGAAGCAGATTCTGCTAATAC1685
association with,CCTGCAAATAGCAGAAATAAAAGAAAAGATTGGAACTAGGTCA
colorectal cancerGCTGAAGATCCTGTGAGCGAAGTTCCAGCAGTGTC
Ilel13O7LysGACACTGCTGGAACTTCGCTCACAGGATCTTCAGCTGACCTA1686
ATA-AAAGTTCCAATCTTTTCTTTTATTTCTGCTATTTGCAGGGTATTAGC
AGAATCTGCTTCCTGTGTCGTCTGATTACATCCTA
AGCAGAAATAAAAGAAA1687
TTTCTTTTATTTCTGCT1688
Adenomatous polyposisCCAAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATA1689
coliTGTTTTTCAAGATGTAGTTCATTATCATCTTTGTCATCAGCTGA
Glu13O9TermAGATGAAATAGGATGTAATCAGACGACACAGGAA
GAA-TAATTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTGATG1690
ACAAAGATGATAATGAACTACATCTTGAAAAACATATTGGAGTA
TCTTCTACACAATAAGTCTGTATTGTTTCTTGG
AGATGTAGTTCATTATC1691
GATAATGAACTACATCT1692
Predisposition toGATTCTGCTAATACCCTGCAAATAGCAGAAATAAAAGAAAAGA1693
Colorectal CancerTTGGAACTAGGTCAGCTGAAGATCCTGTGAGCGAAGTTCCAG
Glu1317GlnCAGTGTCACAGCACCCTAGAACCAAATCCAGCAGAC
GAA-CAAGTCTGCTGGATTTGGTTCTAGGGTGCTGTGACACTGCTGGAA1694
CTTCGCTCACAGGATCTTCAGCTGACCTAGTTCCAATCTTTC
TTTTATTTCTGCTATTTGCAGGGTATTAGCAGAATC
GGTCAGCTGAAGATCCT1695
AGGATCTTCAGCTGACC1696
Adenomatous polyposisAAAGAAAAGATTGGAACTAGGTCAGCTGAAGATCCTGTGAGC1697
coliGAAGTTCCAGCAGTGTCACAGCACCCTAGAACCAAATCCAGC
Gln1328TermAGACTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCA
CAG-TAGTGGCTGATTCTGAAGATAAACTAGAACCCTGCAGTCTGCTGG1698
ATTTGGTTCTAGGGTGCTGTGACACTGCTGGAACTTCGCTCA
CAGGATCTTCAGCTGACCTAGTTCCAATCTTTTCTTT
CAGTGTCACAGCACCCT1699
AGGGTGCTGTGACACTG1700
Adenomatous polyposisGATCCTGTGAGCGAAGTTCCAGCAGTGTCACAGCACCCTAGA1701
coliACCAAATCCAGCAGACTGCAGGGTTCTAGTTTATCTTCAGAAT
Gln1338TermCAGCCAGGCACAAAGCTGTTGAATTTTCTTCAGGAG
CAG-TAGCTCCTGAAGAAAATTCAACAGCTTTGTGCCTGGCTGATTCTGA1702
AGATAAACTAGAACCCTGCAGTCTGCTGGATTTGGTTCTAGG
GTGCTGTGACACTGCTGGAACTTCGCTCACAGGATC
GCAGACTGCAGGGTTCT1703
AGAACCCTGCAGTCTGC1704
Adenomatous polyposisAAGTTCCAGCAGTGTCACAGCACCCTAGAACCAAATCCAGCA1705
coliGACTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCAGGCACAA
Leu1342TermAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTC
TTA-TAAGAGGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTTGTGC1706
CTGGCTGATTCTGAAGATAAACTAGAACCCTGCAGTCTGCTG
GATTTGGTTCTAGGGTGCTGTGACACTGCTGGAACTT
TTCTAGTTTATCTTCAG1707
CTGAAGATAAACTAGAA1708
Adenomatous polyposisCAGCACCCTAGAACCAAATCCAGCAGACTGCAGGGTTCTAGT1709
coliTTATCTTCAGAATCAGCCAGGCACAAAGCTGTTGAATTTTCTT
Arg1348TrpCAGGAGCGAAATCTCCCTCCCGAAAGTGGTGCTCAG
AGG-TGGCTGAGCACCACTTTCGGGAGGGAGATTTCGCTCCTGAAGAAA1710
ATTCAACAGCTTTGTGCCTGGCTGATTCTGAAGATAAACTAGA
ACCCTGCAGTCTGCTGGATTTGGTTCTAGGGTGCTG
AATCAGCCAGGCACAAA1711
TTTGTGCCTGGCTGATT1712
Adenomatous polyposisCTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCAGGCACAAG1713
coliCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTCCCGAAAGTG
Gly1357TermGTGCTCAGACACCCCAAAGTCCACCTGAACACTAT
GGA-TGAATAGTGTTCAGGTGGACTTTGGGGTGTCTGAGCACCACTTTC1714
GGGAGGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTTGT
GCCTGGCTGATTCTGAAGATAAACTAGAACCCTGCAG
TTTCTTCAGGAGCGAAA1715
TTTCGCTCCTGAAGAAA1716
Adenomatous polyposisCCAGGCACAAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCC1717
coliCTCCCGAAAGTGGTGCTCAGACACCCCAAAGTCCACCTGAAC
Gln1367TermACTATGTTCAGGAGACCCCACTCATGTTTAGCAGAT
CAG-TAGATCTGCTAAACATGAGTGGGGTCTCCTGAACATAGTGTTCAG1718
GTGGACTTTGGGGTGTCTGAGCACCACTTTCGGGAGGGAGAT
TTCGCTCCTGAAGAAAATTCAACAGCTTTGTGCCTGG
GTGGTGCTCAGACACCC1719
GGGTGTCTGAGCACCAC1720
Adenomatous polyposisAAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTCCAAAA1721
coliGTGGTGCTCAGACACCCAAAAGTCCACCTGAACACTATGTTC
Lys137OTermAGGAGACCCCACTCATGTTTAGCAGATGTACTTCTG
AAA-TAACAGAAGTACATCTGCTAAACATGAGTGGGGTCTCCTGAACATA1722
GTGTTCAGGTGGACTTTTGGGTGTCTGAGCACCACTTTTGGA
GGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTT
AGACACCCAAAAGTCCA1723
TGGACTTTTGGGTGTCT1724
Adenomatous polyposisCACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA1725
coliGATGTACTTCTGTCAGTTCACTTGATAGTTTTGAGAGTCGTTC
Ser1392TermGATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG
TCA-TAACCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA1726
CTCTCAAAACTATCAAGTGAACTGACAGAAGTACATCTGCTAA
ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG
TGTCAGTTCACTTGATA1727
TATCAAGTGAACTGACA1728
Adenomatous polyposisCACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA1729
coliGATGTACTTCTGTCAGTTCACTTGATAGTTTTGAGAGTCGTTC
Ser1392TermGATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG
TCA-TGACCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA1730
CTCTCAAAACTATCAAGTGAACTGACAGAAGTACATCTGCTAA
ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG
TGTCAGTTCACTTGATA1731
TATCAAGTGAACTGACA1732
Adenomatous polyposisGTTCAGGAGACCCCACTCATGTTTAGCAGATGTACTTCTGTCA1733
coliGTTCACTTGATAGTTTTGAGAGTCGTTCGATTGCCAGCTCCGT
Glu1397TermTCAGAGTGAACCATGCAGTGGAATGGTAGGTGGCA
GAG-TAGTGCCACCTACCATTCCACTGCATGGTTCACTCTGAACGGAGC1734
TGGCAATCGAACGACTCTCAAAACTATCAAGTGAACTGACAGA
AGTACATCTGCTAAACATGAGTGGGGTCTCCTGAAC
ATAGTTTTGAGAGTCGT1735
ACGACTCTCAAAACTAT1736
Adenomatous polyposisCAAACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCT1737
coliCCTCAAACAGCTCAAACCAAGCGAGAAGTACCTAAAAATAAAG
Lys1449TermCACCTACTGCTGAAAAGAGAGAGAGTGGACCTAAGC
AAG-TAGGCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTTATT1738
TTTAGGTACTTCTCGCTTGGTTTGAGCTGTTTGAGGAGGTGGT
GGAGGTGTTTTACTTCTGCTTGGTGGCATGGTTTG
CTCAAACCAAGCGAGAA1739
TTCTCGCTTGGTTTGAG1740
Adenomatous polyposisACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCTCCT1741
coliCAAACAGCTCAAACCAAGCGAGAAGTACCTAAAAATAAAGCAC
Arg1450TenmCTACTGCTGAAAAGAGAGAGAGTGGACCTAAGCAAG
CGA-TGACTTGCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTT1742
ATTTTTAGGTACTTCTCGCTTGGTTTGAGCTGTTTGAGGAGGT
GGTGGAGGTGTTTTACTTCTGCTTGGTGGCATGGT
AAACCAAGCGAGAAGTA1743
TACTTCTCGCTTGGTTT1744
Adenomatous polyposisCAGATGCTGATACTTTATTACATTTTGCCACGGAAAGTACTCC1745
coliAGATGGATTTTCTTGTTCATCCAGCCTGAGTGCTCTGAGCCTC
Ser1503TermGATGAGCCATTTATACAGAAAGATGTGGAATTAAG
TCA-TAACTTAATTCCACATCTTTCTGTATAAATGGCTCATCGAGGCTCA1746
GAGCACTCAGGCTGGATGAACAAGAAAATCCATCTGGAGTAC
TTTCCGTGGCAAAATGTAATAAAGTATCAGCATCTG
TTCTTGTTCATCCAGCC1747
GGCTGGATGAACAAGAA1748
Adenomatous polyposisCTGAGCCTCGATGAGCCATTTATACAGAAAGATGTGGAATTAA1749
coliGAATAATGCCTCCAGTTCAGGAAAATGACAATGGGAATGAAAC
Gln1529TermAGAATCAGAGCAGCCTAAAGAATCAAATGAAAACC
CAG-TAGGGTTTTCATTTGATTCTTTAGGCTGCTCTGATTCTGTTTCATTC1750
CCATTGTCATTTTCCTGAACTGGAGGCATTATTCTTAATTCCAC
ATCTTTCTGTATAAATGGCTCATCGAGGCTCAG
CTCCAGTTCAGGAAAAT1751
ATTTTCCTGAACTGGAG1752
Adenomatous polyposisATGTGGAATTAAGAATAATGCCTCCAGTTCAGGAAAATGACAA1753
coliTGGGAATGAAACAGAATCAGAGCAGCCTAAAGAATCAAATGAA
Ser1539TermAACCAAGAGAAAGAGGCAGAAAAAACTATTGATTC
TCA-TAAGAATCAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTTCATTTGA1754
TTCTTTAGGCTGCTCTGATTCTGTTTCATTCCCATTGTCATTTT
CCTGAACTGGAGGCATTATTCTTAATTCCACAT
AACAGAATCAGAGCAGC1755
GCTGCTCTGATTCTGTT1756
Adenomatous polyposisAAAACCAAGAGAAAGAGGCAGAAAAAACTATTGATTCTGAAAA1757
coliGGACCTATTAGATGATTCAGATGATGATGATATTGAAATACTA
Ser1567TermGAAGAATGTATTATTTCTGCCATGCCAACAAAGTC
TCA-TGAGACTTTGTTGGCATGGCAGAAATAATACATTCTTCTAGTATTTC1758
AATATCATCATCATCTGAATCATCTAATAGGTCCTTTTCAGAAT
CAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTT
AGATGATTCAGATGATG1759
CATCATCTGAATCATCT1760
Adenomatous polyposisAGAGAGTTTTCTCAGACAACAAAGATTCAAAGAAACAGAATTT1761
coliGAAAAATAATTCCAAGGACTTCAATGATAAGCTCCCAAATAAT
Asp1822ValGAAGATAGAGTCAGAGGAAGTTTTGCTTTTGATTC
GAC-GTCGAATCAAAAGCAAAACTTCCTCTGACTCTATCTTCATTATTTGG1762
GAGCTTATCATTGAAGTCCTTGGAATTATTTTTCAAATTCTGT
TCTTTGAATCTTTGTTGTCTGAGAAAACTCTCT
TTCCAAGGACTTCAATG1763
CATTGAAGTCCTTGGAA1764
Adenomatous polyposisAAAACTGACAGCACAGAATCCAGTGGAACCCAAAGTCCTAAG1765
coliCGCCATTCTGGGTCTTACCTTGTGACATCTGTTTAAAAGAGAG
Leu2839PheGAAGAATGAAACTAAGAAAATTCTATGTTAATTACA
CTT-TTTTGTAATTAACATAGAATTTTCTTAGTTTCATTCTTCCTCTCTTTT1766
AAACAGATGTCACAAGGTAAGACCCAGAATGGCGCTTAGGAC
TTTGGGTTCCACTGGATTCTGTGCTGTCAGTTTT
GGTCTTACCTTGTGACA1767
TGTCACAAGGTAAGACC1768
|
Parahemophilia—Factor V Deficiency
[0137] Deficiency in clotting Factor V is associated with a lifelong predisposition to thrombosis. The disease typically manifests itself with usually mild bleeding, although bleeding times and clotting times are consistently prolonged. Individuals that are heterozygous for a mulation in Factor V have lowered levels of factor V but probably never have abnormal bleeding. A large number of alleles with a range of presenting symptoms have been identified. The attached table disclosed the correcting oligonucleotide base sequences for the Factor V oligonucleotides of the invention.
20TABLE 19
|
|
Factor V Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Factor V deficiencyTTGACTGAATGCTTATTTTGGCCTGTGTCTCTCCCTCTTTCTCA1768
Ala221ValGATATAACAGTTTGTGCCCATGACCACATCAGCTGGCATCTGC
GCC-GTCTGGGAATGAGCTCGGGGCCAGAATTATTCTCCAT
ATGGAGAATAATTCTGGCCCCGAGCTCATTCCCAGCAGATGC1769
CAGCTGATGTGGTCATGGGCACAAACTGTTATATCTGAGAAAG
AGGGAGAGACACAGGCCAAAATAAGCATTCAGTCAA
AGTTTGTGCCCATGACC1770
GGTCATGGGCACAAACT1771
ThrombosisTGTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAA1772
Arg3O6GlyACTGCCCAAAGAAAACCAGGAATCTTAAGAAAATAACTCGTGA
AGG-GGGGCAGAGGCGGCACATGAAGAGGTGGGAATACTTCA
TGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGAGT1773
TATTTTCTTAAGATTCCTGGTTTTCTTTGGGCAGTTTTTAATGT
CAATGTAAGCCTGCATCCCAGCTGAGTTAGGACA
AGAAAACCAGGAATCTT1774
AAGATTCCTGGTTTTCT1775
ThrombosisGTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAAA1776
Arg306ThrCTGCCCAAAGAAAACCAGGAATCTTAAGAAAATAACTCGTGAG
AGG-ACGCAGAGGCGGCACATGAAGAGGTGGGAATACTTCAT
ATGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGA1777
GTTATTTTCTTAAGATTCCTGGTTTTCTTTGGGCAGTTTTTAAT
GTCAATGTAAGCCTGCATCCCAGCTGAGTTAGGAC
GAAAACCAGGAATCTTA1778
TAAGATTCCTGGTTTTC1779
Increased RiskCCACAGAAAATGATGCCCAGTGCTTAACAAGACCATACTACAG1780
ThrombosisTGACGTGGACATCATGAGAGACATCGCCTCTGGGCTAATAGG
Arg485LysACTACTTCTAATCTGTAAGAGCAGATCCCTGGACAG
AGA-AAACTGTCCAGGGATCTGCTCTTACAGATTAGAAGTAGTCCTATTA1781
GCCCAGAGGCGATGTCTCTCATGATGTCCACGTCACTGTAGT
ATGGTCTTGTTAAGCACTGGGCATCATTTTCTGTGG
CATCATGAGAGACATCG1782
CGATGTCTCTCATGATG1783
Increased RiskACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGAG1784
ThrombosisCAGATCCCTGGACAGGCGAGGAATACAGGTATTTTGTCCTTG
Arg506GlnAAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTGG
CGA-CAACCAGAAGAAATTCTCAGAATTTCTGAAAGGTTACTTCAAGGAC1785
AAAATACCTGTATTCCTCGCCTGTCCAGGGATCTGCTCTTACA
GATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGT
GGACAGGCGAGGAATAC1786
GTATTCCTCGCCTGTCC1787
Factor V DeficiencyGACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGA1788
Arg506TermGCAGATCCCTGGACAGGCGAGGAATACAGGTATTTTGTCCTT
CGA-TGAGAAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTG
CAGAAGAAATTCTCAGAATTTCTGAAAGGTTACTTCAAGGACA1789
AAATACCTGTATTCCTCGCCTGTCCAGGGATCTGCTCTTACAG
ATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGTC
TGGACAGGCGAGGAATA1790
TATTCCTCGCCTGTCCA1791
ThrombosisAGTGATGCTGACTATGATTACCAGAACAGACTGGCTGCAGCA1792
Arg712TermTTAGGAATCAGGTCATTCCGAAACTCATCATTGAATCAGGAAG
CGA-TGAAAGAAGAGTTCAATCTTACTGCCCTAGCTCTGGAGA
TCTCCAGAGCTAGGGCAGTAAGATTGAACTCTTCTTCTTCCTG1793
ATTCAATGATGAGTTTCGGAATGACCTGATTCCTAATGCTGCA
GCCAGTCTGTTCTGGTAATCATAGTCAGCATCACT
GGTCATTCCGAAACTCA1794
TGAGTTTCGGAATGACC1795
ThrombosisTCAGTCAGACAAACCTTTCCCCAGCCCTCGGTCAGATGCCCA1796
His1299ArgTTTCTCCAGACCTCAGCCATACAACCCTTTCTCTAGACTTCAG
CAT-CGTCCAGACAAACCTCTCTCCAGAACTCAGTCAAACAAA
TTTGTTTGACTGAGTTCTGGAGAGAGGTTTGTCTGGCTGAAGT1797
CTAGAGAAAGGGTTGTATGGCTGAGGTCTGGAGAAATGGGCA
TCTGACCGAGGGCTGGGGAAAGGTTTGTCTGACTGA
CCTCAGCCATACAACCC1798
GGGTTGTATGGCTGAGG1799
|
Hemophilia—Factor VIII Deficiency
[0138] The attached table discloses the correcting oligonucleotide base sequences for the Factor VIII oligonucleotides of the invention.
21TABLE 20
|
|
Factor VIII Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Haemophilia AAGCTCTCCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTT1800
Tyr5CysTAGTGCCACCAGAAGATACTACCTGGGTGCAGTGGAACTGTC
TAC-TGCATGGGACTATATGCAAAGTGATCTCGGTGAGCTGCC
GGCAGCTCACCGAGATCACTTTGCATATAGTCCCATGACAGT1801
TCCACTGCACCCAGGTAGTATCTTCTGGTGGCACTAAAGCAG
AATCGCAAAAGGCACAGAAAGAAGCAGGTGGAGAGCT
CAGAAGATACTACCTGG1802
CCAGGTAGTATCTTCTG1803
Haemophilia ACCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTTTAGTGC1804
Leu7ArgCACCAGAAGATACTACCTGGGTGCAGTGGAACTGTCATGGGA
CTG-CGGCTATATGCAAAGTGATCTCGGTGAGCTGCCTGTGGA
TCCACAGGCAGCTCACCGAGATCACTTTGCATATAGTCCCAT1805
GACAGTTCCACTGCACCCAGGTAGTATCTTCTGGTGGCACTA
AAGCAGAATCGCAAAAGGCACAGAAAGAAGCAGGTGG
ATACTACCTGGGTGCAG1806
CTGCACCCAGGTAGTAT1807
Haemophilia AAGTCATGCAAATAGAGCTCTCCACCTGCTTCTTTCTGTGCCTT1808
Ser(-1)ArgTTGCGATTCTGCTTTAGTGCCACCAGAAGATACTACCTGGGT
AGTg-AGGGCAGTGGAACTGTCATGGGACTATATGCAAAGTGAT
ATCACTTTGCATATAGTCCCATGACAGTTCCACTGCACCCAG1809
GTAGTATCTTCTGGTGGCACTAAAGCAGAATCGCAAAAGGCA
CAGAAAGAAGCAGGTGGAGAGCTCTATTTGCATGACT
TGCTTTAGTGCCACCAG1810
CTGGTGGCACTAAAGCA1811
Haemophilia ACATTTGTAGCAATAAGTCATGCAAATAGAGCTCTCCACCTGCT1812
Arg(-5)TermTCTTTCTGTGCCTTTTGCGATTCTGCTTTAGTGCCACCAGAAG
gCGA-TGAATACTACCTGGGTGCAGTGGAACTGTCATGGGACT
AGTCCCATGACAGTTCCACTGCACCCAGGTAGTATCTTCTGG1813
TGGCACTAAAGCAGAATCGCAAAAGGCACAGAAAGAAGCAGG
TGGAGAGCTCTATTTGCATGACTTATTGCTACAAATG
GCCTTTTGCGATTCTGC1814
GCAGAATCGCAAAAGGC1815
Haemophilia ATTCTGTGCCTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATA1816
Glu11ValCTACCTGGGTGCAGTGGAACTGTCATGGGACTATATGCAAAG
GAA-GTATGATCTCGGTGAGCTGCCTGTGGACGCAAGGTAAAG
CTTTACCTTGCGTCCACAGGCAGCTCACCGAGATCACTTTGC1817
ATATAGTCCCATGACAGTTCCACTGCACCCAGGTAGTATCTTC
TGGTGGCACTAAAGCAGAATCGCAAAAGGCACAGAA
TGCAGTGGAACTGTCAT1818
ATGACAGTTCCACTGCA1819
Haemophilia ACTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATACTACCTGG1820
Trp14GlyGTGCAGTGGAACTGTCATGGGACTATATGCAAAGTGATCTCG
aTGG-GGGGTGAGCTGCCTGTGGACGCAAGGTAAAGGCATGTCC
GGACATGCCTTTACCTTGCGTCCACAGGCAGCTCACCGAGAT1821
CACTTTGCATATAGTCCCATGACAGTTCCACTGCACCCAGGT
AGTATCTTCTGGTGGCACTAAAGCAGAATCGCAAAAG
AACTGTCATGGGACTAT1822
ATAGTCCCATGACAGTT1823
Haemophilia ATTCACGCAGATTTCCTCCTAGAGTGCCAAAATCTTTTCCATTC1824
Tyr46TermAACACCTCAGTCGTGTACAAAAAGACTCTGTTTGTAGAATTCA
TACa-TAACGGATCACCTTTTCAACATCGCTAAGCCAAGGCCA
TGGCCTTGGCTTAGCGATGTTGAAAAGGTGATCCGTGAATTC1825
TACAAACAGAGTCTTTTTGTACACGACTGAGGTGTTGAATGGA
AAAGATTTTGGCACTCTAGGAGGAAATCTGCGTGAA
GTCGTGTACAAAAAGAC1826
GTCTTTTTGTACACGAC1827
Haemophilia AATCTTTTCCATTCAACACCTCAGTCGTGTACAAAAAGACTCTG1828
Asp56GluTTTGTAGAATTCACGGATCACCTTTTCAACATCGCTAAGCCAA
GATc-GAAGGCCACCCTGGATGGGTAATGAAAACAATGTTGAA
TTCAACATTGTTTTCATTACCCATCCAGGGTGGCCTTGGCTTA1829
GCGATGTTGAAAAGGTGATCCGTGAATTCTACAAACAGAGTC
TTTTTGTACACGACTGAGGTGTGTTGAATGGAAAAGAT
TTCACGGATCACCTTTT1830
AAAAGGTGATCCGTGAA1831
Haemophilia ATTCTGGAGTACTATCCCCAAGTAACCTTTGGCGGACATCTCAT1832
Gly73ValTCTTACAGGTCTGCTAGGTCCTACCATCCAGGCTGAGGTTTA
GGT-GTTTGATACAGTGGTCATTACACTTAAGAACATGGCTTC
GAAGCCATGTTCTTAAGTGTAATGACCACTGTATCATAAACCT1833
CAGCCTGGATGGTAGGACCTAGCAGACCTGTAAGAATGAGAT
GTCCGCCAAAGGTTACTTGGGGATAGTACTCCAGAA
TCTGCTAGGTCCTACCA1834
TGGTAGGACCTAGCAGA1835
Haemophilia ACAAGTAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAG1836
Glu79LysGTCCTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTAC
tGAG-AAGACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTC
GAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTAATGA1837
CCACTGTATCATAAACCTCAGCCTGGATGGTAGGACCTAGCA
GACCTGTAAGAATGAGATGTCCGCCAAAGGTTACTTG
TCCAGGCTGAGGTTTAT1838
ATAAACCTCAGCCTGGA1839
Haemophilia ATAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCC1840
Val8OAspTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACACTT
GTT-GATAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGC
GCATGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTA1841
ATGACCACTGTATCATAAACCTCAGCCTGGATGGTAGGACCT
AGCAGACCTGTAAGAATGAGATGTCCGCCAAAGGTTA
GGCTGAGGTTTATGATA1842
TATCATAAACCTCAGCC1843
Haemophilia ATTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT1844
Asp82ValCCAGGCTGAGGTTTATGATACAGTGGTCATTACACTTAAGAAC
GAT-GTTATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGG
CCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA1845
AGTGTAATGACCACTGTATCATAAACCTCAGCCTGGATGGTA
GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA
GGTTTATGATACAGTGG1846
CCACTGTATCATAAACC1847
Haemophilia ATTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT1848
Asp82GlyCCAGGCTGAGGTTTATGATACAGTGGTCATTACACTTAAGAAC
GAT-GGTATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGG
CCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA1849
AGTGTAATGACCACTGTATCATAAACCTCAGCCTGGATGGTA
GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA
GGTTTATGATACAGTGG1850
CCACTGTATCATAAACC1851
Haemophilia AATCTCATTCTTACAGGTCTGCTAGGTCCTACCATCCAGGCTGA1852
Val85AspGGTTTATGATACAGTGGTCATTACACTTAAGAACATGGCTTCC
GTC-GACCATCCTGTCAGTCTTCATGCTGTTGGTGTATCCTA
TAGGATACACCAACAGCATGAAGACTGACAGGATGGGAAGCC1853
ATGTTCTTAAGTGTAATGACCACTGTATCATAAACCTCAGCCT
GGATGGTAGGACCTAGCAGACCTGTAAGAATGAGAT
TACAGTGGTCATTACAC1854
GTGTAATGACCACTGTA1855
Haemophilia ACAGGTCTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATA1856
Lys89ThrCAGTGGTCATTACACTTAAGAACATGGCTTCCCATCCTGTCA
AAG-ACGGTCTTCATGCTGTTGGTGTATCCTACTGGAAAGCTTC
GAAGCTTTCCAGTAGGATACACCAACAGCATGAAGACTGACA1857
GGATGGGAAGCCATGTTCTTAAGTGTAATGACCACTGTATCAT
AAACCTCAGCCTGGATGGTAGGACCTAGCAGACCTG
TACACTTAAGAACATGG1858
CCATGTTCTTAAGTGTA1859
Haemophilia ACTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATACAGTG1860
Met91ValGTCATTACACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTC
cATG-GTGATGCTGTTGGTGTATCCTACTGGAAAGCTTCTGAGG
CCTCAGAAGCTTTCCAGTAGGATACACCAACAGCATGAAGAC1861
TGACAGGATGGGAAGCCATGTTCTTAAGTGTAATGACCACTG
TATCATAAACCTCAGCCTGGATGGTAGGACCTAGCAG
TTAAGAACATGGCTTCC1862
GGAAGCCATGTTCTTAA1863
Haemophilia ACTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACACT1864
His94ArgTAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGGT
CAT-CGTGTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAAA
TTTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAG1865
CATGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTAA
TGACCACTGTATCATAAACCTCAGCCTGGATGGTAG
GGCTTCCCATCCTGTCA1866
TGACAGGATGGGAAGCC1867
Haemophilia ACCTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACAC1868
His94TyrTTAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGG
cCAT-TATTGTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAA
TTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAGC1869
ATGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTAAT
GACCACTGTATCATAAACCTCAGCCTGGATGGTAGG
TGGCTTCCCATCCTGTC1870
GACAGGATGGGAAGCCA1871
Haemophilia ACTGAGGTTTATGATACAGTGGTCATTACACTTAAGAACATGGC1872
Leu98ArgTTCCCATCCTGTCAGTCTTCATGCTGTTGGTGTATCCTACTGG
CTT-CGTAAAGCTTCTGAGGGTGAGTAAAATACCCTCCTATT
AATAGGAGGGTATTTTACTCACCCTCAGAAGCTTTCCAGTAGG1873
ATACACCAACAGCATGAAGACTGACAGGATGGGAAGCCATGT
TCTTAAGTGTAATGACCACTGTATCATAAACCTCAG
TGTCAGTCTTCATGCTG1874
CAGCATGAAGACTGACA1875
Haemophilia AGATACAGTGGTCATTACACTTAAGAACATGGCTTCCCATCCTG1876
Gly1O2SerTCAGTCTTCATGCTGTTGGTGTATCCTACTGGAAAGCTTCTGA
tGGT-AGTGGGTGAGTAAAATACCCTCCTATTGTCCTGTCATT
AATGACAGGACAATAGGAGGGTATTTTACTCACCCTCAGAAG1877
CTTTCCAGTAGGATACACCAACAGCATGAAGACTGACAGGAT
GGGAAGCCATGTTCTTAAGTGTAATGACCACTGTATC
ATGCTGTTGGTGTATCC1878
GGATACACCAACAGCAT1879
Haemophilia ACTTTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTC1880
Glu113AspCTGCTATAGGAGCTGAATATGATGATCAGACCAGTCAAAGGG
GAAt-GACAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGC
GCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGA1881
CTGGTCTGATCATCATATTCAGCTCCTATAGCAGGAAGAAATA
AAATTGTCCTTTCTATATCCACTGTACACTCAAAG
GGAGCTGAATATGATGA1882
TCATCATATTCAGCTCC1883
Haemophilia ATTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTCCT1884
Tyr114CysGCTATAGGAGCTGAATATGATGATCAGACCAGTCAAAGGGAG
TAT-TGTAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCCA
TGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT1885
GACTGGTCTGATCATCATATTCAGCTCCTATAGCAGGAAGAAA
TAAAATTGTCCTTTCTATATCCACTGTACACTCAA
AGCTGAATATGATGATC1886
GATCATCATATTCAGCT1887
Haemophilia AGTACAGTGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATA1888
Asp116GlyGGAGCTGAATATGATGATCAGACCAGTCAAAGGGAGAAAGAA
GAT-GGTGATGATAAAGTCTTCCCTGGTGGAAGCCATACATA
TATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCT1889
CCCTTTGACTGGTCTGATCATCATATTCAGCTCCTATAGCAGG
AAGAAATAAAATTGTCCTTTCTATATCCACTGTAC
ATATGATGATCAGACCA1890
TGGTCTGATCATCATAT1891
Haemophilia AACAGTGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAG1892
Gln117TermGAGCTGAATATGATGATCAGACCAGTCAAAGGGAGAAAGAAG
tCAG-TAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATG
CATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTT1893
CTCCCTTTGACTGGTCTGATCATCATATTCAGCTCCTATAGCA
GGAAGAAATAAAATTGTCCTTTCTATATCCACTGT
ATGATGATCAGACCAGT1894
ACTGGTCTGATCATCAT1895
Haemophilia ATGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAGGAGC1896
Thr118lleTGAATATGATGATCAGACCAGTCAAAGGGAGAAAGAAGATGA
ACC-ATCTAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTG
CAGACATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTT1897
CTTTCTCCCTTTGACTGGTCTGATCATCATATTCAGCTCCTAT
AGCAGGAAGAAATAAAATTGTCCTTTCTATATCCA
TGATCAGACCAGTCAAA1898
TTTGACTGGTCTGATCA1899
Haemophilia AAGGACAATTTTATTTCTTCCTGCTATAGGAGCTGAATATGATG1900
Glu122TermATCAGACCAGTCAAAGGGAGAAAGAAGATGATAAAGTCTTCC
gGAG-TAGCTGGTGGAAGCCATACATATGTCTGGCAGGTCCTGA
TCAGGACCTGCCAGACATATGTATGGCTTCCACCAGGGAAGA1901
CTTTATCATCTTCTTTCTCCCTTTGACTGGTCTGATCATCATAT
TCAGCTCCTATAGCAGGAAGAAATAAAATTGTCCT
GTCAAAGGGAGAAAGAA1902
TTCTTTCTCCCTTTGAC1903
Haemophilia ATTTCTTCCTGCTATAGGAGCTGAATATGATGATCAGACCAGTC1904
Asp126HisAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCC
tGAT-CATATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTC
GACCATTCTCTTTCAGGACCTGCCAGACATATGTATGGCTTCC1905
ACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGACTGGTC
TGATCATCATATTCAGCTCCTATAGCAGGAAGAAA
AAGAAGATGATAAAGTC1906
GACTTTATCATCTTCTT1907
Haemophilia AAGTCAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGA1908
Gln139TermAGCCATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCCA
gCAG-TAGATGGCCTCTGACCCACTGTGCCTTACCTACTCATATC
GATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTGGA1909
CCATTCTCTTTCAGGACCTGCCAGACATATGTATGGCTTCCAC
CAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGACT
ATGTCTGGCAGGTCCTG1910
CAGGACCTGCCAGACAT1911
Haemophilia AAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCC1912
Val14OAIaATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGG
GTC-GCCCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTC
GAAAGATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATT1913
GGACCATTCTCTTTCAGGACCTGCCAGACATATGTATGGCTT
CCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT
CTGGCAGGTCCTGAAAG1914
CTTTCAGGACCTGCCAG1915
Haemophilia AAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTG1916
Asn144LysGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACT
AATg-AAAGTGCCTTACCTACTCATATCTTTCTCATGTGGACCTG
CAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGTGG1917
GTCAGAGGCCATTGGACCATTCTCTTTCAGGACCTGCCAGAC
ATATGTATGGCTTCCACCAGGGAAGACTTTATCATCT
AAAGAGAATGGTCCAAT1918
ATTGGACCATTCTCTTT1919
Haemophilia AGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA1920
Gly145AspGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTG
GGT-GATCCTTACCTACTCATATCTTTCTCATGTGGACCTGGT
ACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT1921
GGGTCAGAGGCCATTGGACCATTCTCTTTCAGGACCTGCCAG
ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT
AGAGAATGGTCCAATGG1922
CCATTGGACCATTCTCT1923
Haemophilia AATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA1924
Gly145ValGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTG
GGT-GTTCCTTACCTACTCATATCTTTCTCATGTGGACCTGGT
ACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT1925
GGGTCAGAGGCCATTGGACCATTCTCTTTCAGGACCTGCCAG
ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT
AGAGAATGGTCCAATGG1926
CCATTGGACCATTCTCT1927
Haemophilia AGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCAG1928
Pro146SerGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGC
tCCA-TCACTTACCTACTCATATCTTTCTCATGTGGACCTGGTAA
TTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACA1929
GTGGGTCAGAGGCCATTGGACCATTCTCTTTCAGGACCTGCC
AGACATATGTATGGCTTCCACCAGGGAAGACTTTATC
AGAATGGTCCAATGGCC1930
GGCCATTGGACCATTCT1931
Haemophilia ACCATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAAT1932
Cys153TrpGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTCTCAT
TGCc-TGGGTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATT
AATGAGGCCTGAATTCAAGTCTTTTACCAGGTCCACATGAGAA1933
AGATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTGGA
CCATTCTCTTTCAGGACCTGCCAGACATATGTATGG
CCACTGTGCCTTACCTA1934
TAGGTAAGGCACAGTGG1935
Haemophilia ATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGA1936
Tyr156TermCCCACTGTGCCTTACCTACTCATATCTTTCTCATGTGGACCTG
TACt-TAAGTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTA
TAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGTC1937
CACATGAGAAAGATATGAGTAGGTAAGGCACAGTGGGTCAGA
GGCCATTGGACCATTCTCTTTCAGGACCTGCCAGACA
CTTACCTACTCATATCT1938
AGATATGAGTAGGTAAG1939
Haemophilia AGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGAC1940
Ser157ProCCACTGTGCCTTACCTACTCATATCTTTCTCATGTGGACCTGG
cTCA-CCATAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTAC
GTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGT1941
CCACATGAGAAAGATATGAGTAGGTAAGGCACAGTGGGTCAG
AGGCCATTGGACCATTCTCTTTCAGGACCTGCCAGAC
TTACCTACTCATATCTT1942
AAGATATGAGTAGGTAA1943
Haemophilia AGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGC1944
Ser16OProCTTACCTACTCATATCTTTCTCATGTGGACCTGGTAAAAGACT
tTCT-CCTTGAATTCAGGCCTCATTGGAGCCCTACTAGTATGTA
TACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTT1945
TACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAG
TGGGTCAGAGGCCATTGGACCATTCTCTTTCAGGAC
CATATCTTTCTCATGTG1946
CACATGAGAAAGATATG1947
Haemophilia AAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGCCTTACC1948
Val162MetTACTCATATCTTTCTCATGTGGACCTGGTAAAAGACTTGAATT
tGTG-ATGCAGGCCTCATTGGAGCCCTACTAGTATGTAGAGAAG
CTTCTCTACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAA1949
GTCTTTTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAG
GCACAGTGGGTCAGAGGCCATTGGACCATTCTCTTT
TTTCTCATGTGGACCTG1950
CAGGTCCACATGAGAAA1951
Haemophilia ACAATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTC1952
Lys166ThrTCATGTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATTGG
AAA-ACAAGCCCTACTAGTATGTAGAGAAGGTAAGTGTATGAA
TTCATACACTTACCTTCTCTACATACTAGTAGGGCTCCAATGA1953
GGCCTGAATTCAAGTCTTTTACCAGGTCCACATGAGAAAGATA
TGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTG
CCTGGTAAAAGACTTGA1954
TCAAGTCTTTTACCAGG1955
Haemophilia AACCCACTGTGCCTTACCTACTCATATCTTTCTCATGTGGACCT1956
Ser17OLeuGGTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTACTAGT
TCA-TTAATGTAGAGAAGGTAAGTGTATGAAAGCGTAGGATTG
CAATCCTACGCTTTCATACACTTACCTTCTCTACATACTAGTAG1957
GGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGTCCAC
ATGAGAAAGATATGAGTAGGTAAGGCACAGTGGGT
CTTGAATTCAGGCCTCA1958
TGAGGCCTGAATTCAAG1959
Haemophilia AAATGTTCTCACTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGA1960
Phe195ValCACAGACCTTGCACAAATTTATACTACTTTTTGCTGTATTTGAT
aTTT-GTTGAAGGTTAGTGAGTCTTAATCTGAATTTTGGATT
AATCCAAAATTCAGATTAAGACTCACTAACCTTCATCAAATACA1961
GCAAAAAGTAGTATAAATTTGTGCAAGGTCTGTGTCTTTTCCT
TGGCCAGACTCCCTGAAAAAGAAGTGAGAACATT
TGCACAAATTTATACTA1962
TAGTATAAATTTGTGCA1963
Haemophilia ACTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCT1964
Leu198HisTGCACAAATTTATACTACTTTTTGCTGTATTTGATGAAGGTTAG
CTT-CATTGAGTCTTAATCTGAATTTTGGATTCCTGAAAGAA
TTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTAACCTTC1965
ATCAAATACAGCAAAAAGTAGTATAAATTTGTGCAAGGTCTGT
GTCTTTTCCTTGGCCAGACTCCCTGAAAAAGAAG
TATACTACTTTTTGCTG1966
CAGCAAAAAGTAGTATA1967
Haemophilia ATTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCACA1968
Ala200AspAATTTATACTACTTTTTGCTGTATTTGATGAAGGTTAGTGAGTC
GCT-GATTTAATCTGAATTTTGGATTCCTGAAAGAAATCCTC
GAGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACT1969
AACCTTCATCAAATACAGCAAAAAGTAGTATAAATTTGTGCAA
GGTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAA
ACTTTTTGCTGTATTTG1970
CAAATACAGCAAAAAGT1971
Haemophilia ATTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCAC1972
Ala200ThrAAATTTATACTACTTTTTGCTGTATTTGATGAAGGTTAGTGAGT
tGCT-ACTCTTAATCTGAATTTTGGATTCCTGAAAGAAATCCT
AGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTA1973
ACCTTCATCAAATACAGCAAAAAGTAGTATAAATTTGTGCAAG
GTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAAA
TACTTTTTGCTGTATTT1974
AAATACAGCAAAAAGTA1975
Haemophilia AAACTCCTTGATGCAGGATAGGGATGCTGCATCTGCTCGGGCC1976
Val234PheTGGCCTAAAATGCACACAGTCAATGGTTATGTAAACAGGTCTC
aGTC-TTCTGCCAGGTATGTACACACCTGCTCAACAATCCTCAG
CTGAGGATTGTTGAGCAGGTGTGTACATACCTGGCAGAGACC1977
TGTTTACATAACCATTGACTGTGTGCATTTTAGGCCAGGCCCG
AGCAGATGCAGCATCCCTATCCTGCATCAAGGAGTT
TGCACACAGTCAATGGT1978
ACCATTGACTGTGTGCA1979
Haemophilia AATTTCAGATTCTCTACTTCATAGCCATAGGTGTCTTATTCCTAC1980
Gly247GluTTTACAGGTCTGATTGGATGCCACAGGAAATCAGTCTATTGGC
GGA-GAAATGTGATTGGAATGGGCACCACTCCTGAAGTGCA
TGCACTTCAGGAGTGGTGCCCATTCCAATCACATGCCAATAG1981
ACTGATTTCCTGTGGCATCCAATCAGACCTGTAAAGTAGGAAT
AAGACACCTATGGCTATGAAGTAGAGAATCTGAAAT
TCTGATTGGATGCCACA1982
TGTGGCATCCAATCAGA1983
Haemophilia AATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC1984
Trp255CysAGGAAATCAGTCTATTGGCATGTGATTGGAATGGGCACCACT
TGGc-TGTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACA
TGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT1985
GCCCATTCCAATCACATGCCAATAGACTGATTTCCTGTGGCAT
CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT
GTCTATTGGCATGTGAT1986
ATCACATGCCAATAGAC1987
Haemophilia AATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC1988
Trp255TermAGGAAATCAGTCTATTGGCATGTGATTGGAATGGGCACCACT
TGGc-TGACCTGAAGTGCACTCAATATTCCTCGAAGGTCACACA
TGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT1989
GCCCATTCCAATCACATGCCAATAGACTGATTTCCTGTGGCAT
CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT
GTCTATTGGCATGTGAT1990
ATCACATGCCAATAGAC1991
Haemophilia AAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCACAG1992
His256LeuGAAATCAGTCTATTGGCATGTGATTGGAATGGGCACCACTCC
CAT-CTTTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT
AATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTG1993
GTGCCCATTCCAATCACATGCCAATAGACTGATTTCCTGTGG
CATCCAATCAGACCTGTAAAGTAGGAATAAGACACCT
CTATTGGCATGTGATTG1994
CAATCACATGCCAATAG1995
Haemophilia ATATTCCTACTTTACAGGTCTGATTGGATGCCACAGGAAATCAG1996
Gly259ArgTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAAGTGC
tGGA-AGAACTCAATATTCCTCGAAGGTCACACATTTCTTGTGA
TCACAAGAAATGTGTGACCTTCGAGGAATATTGAGTGCACTTC1997
AGGAGTGGTGCCCATTCCAATCACATGCCAATAGACTGATTT
CCTGTGGCATCCAATCAGACCTGTAAAGTAGGAATA
ATGTGATTGGAATGGGC1998
GCCCATTCCAATCACAT1999
Haemophilia ATTGGATGCCACAGGAAATCAGTCTATTGGCATGTGATTGGAAT2000
Val266GlyGGGCACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCA
GTG-GGGCACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTT
AAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGACCT2001
TCGAGGAATATTGAGTGCACTTCAGGAGTGGTGCCCATTCCA
ATCACATGCCAATAGACTGATTTCCTGTGGCATCCAA
TCCTGAAGTGCACTCAA2002
TTGAGTGCACTTCAGGA2003
Haemophilia ACAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAAG2004
Glu272GlyTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGTGAGGAA
GAA-GGACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAAC
GTTATTGGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTC2005
ACAAGAAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAG
GAGTGGTGCCCATTCCAATCACATGCCAATAGACTG
ATTCCTCGAAGGTCACA2006
TGTGACCTTCGAGGAAT2007
Haemophilia ATCAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAA2008
Glu272LysGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGTGAGGA
cGAA-AAAACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAA
TTATTGGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTCA2009
CAAGAAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAG
GAGTGGTGCCCATTCCAATCACATGCCAATAGACTGA
TATTCCTCGAAGGTCAC2010
GTGACCTTCGAGGAATA2011
Haemophilia AGGCATGTGATTGGAATGGGCACCACTCCTGAAGTGCACTCAA2012
Thr275lleTATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCATCGCCA
ACA-ATAGGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTAC
GTAAGGAAAGTTATTGGCGAGATTTCCAAGGACGCCTGGCGA2013
TGGTTCCTCACAAGAAATGTGTGACCTTCGAGGAATATTGAGT
GCACTTCAGGAGTGGTGCCCATTCCAATCACATGCC
AGGTCACACATTTCTTG2014
CAAGAAATGTGTGACCT2015
Haemophilia ATTGGAATGGGCACCACTCCTGAAGTGCACTCAATATTCCTCG2016
Val278AlaAAGGTCACACATTTCTTGTGAGGAACCATCGCCAGGCGTCCT
GTG-GCGTGGAAATCTCGCCAATAACTTTCCTTACTGCTCAAAC
GTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCAAGGAC2017
GCCTGGCGATGGTTCCTCACAAGAAATGTGTGACCTTCGAGG
AATATTGAGTGCACTTCAGGAGTGGTGCCCATTCCAA
ATTTCTTGTGAGGAACC2018
GGTTCCTCACAAGAAAT2019
Haemophilia ATGGGCACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTC2020
Asn28OlleACACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAA
AAC-ATCTCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTT
AAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCA2021
AGGACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGACCTT
CGAGGAATATTGAGTGCACTTCAGGAGTGGTGCCCA
TGTGAGGAACCATCGCC2022
GGCGATGGTTCCTCACA2023
Haemophilia AACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACAT2024
Arg282CysTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGC
tCGC-TGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGG
CCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA2025
TTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTGT
GACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT
GGAACCATCGCCAGGCG2026
CGCCTGGCGATGGTTCC2027
Haemophilia ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT2028
Arg282HisTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGCC
CGC-CACAATAACTTTCCTTACTGCTCAAACACTCTTGATGGA
TCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG2029
ATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTG
TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG
GAACCATCGCCAGGCGT2030
ACGCCTGGCGATGGTTC2031
Haemophilia ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT2032
Arg282LeuTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGCC
CGC-CTCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGA
TCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG2033
ATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTG
TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG
GAACCATCGCCAGGCGT2034
ACGCCTGGCGATGGTTC2035
Haemophilia ACTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGT2036
Ala284GluGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAAC
GCG-GAGTTTCCTTACTGCTCAAACACTCTTGATGGACCTTGG
CCAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATT2037
GGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAG
AAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAG
TCGCCAGGCGTCCTTGG2038
CCAAGGACGCCTGGCGA2039
Haemophilia ACCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTG2040
Ala284ProTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAA
gGCG-CCGCTTTCCTTACTGCTCAAACACTCTTGATGGACCTTG
CAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTG2041
GCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAA
ATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGG
ATCGCCAGGCGTCCTTG2042
CAAGGACGCCTGGCGAT2043
Haemophilia ATATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCATCGCCA2044
Ser289LeuGGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTACTGCTCAA
TCG-TTGACACTCTTGATGGACCTTGGACAGTTTCTACTGTT
AACAGTAGAAACTGTCCAAGGTCCATCAAGAGTGTTTGAGCA2045
GTAAGGAAAGTTATTGGCGAGATTTCCAAGGACGCCTGGCGA
TGGTTCCTCACAAGAAATGTGTGACCTTCGAGGAATA
GGAAATCTCGCCAATAA2046
TTATTGGCGAGATTTCC2047
Haemophilia AGTCACACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGG2048
Phe293SerAAATCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGAT
TTC-TCCGGACCTTGGACAGTTTCTACTGTTTTGTCATATCTC
GAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCATCAAG2049
AGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCAAG
GACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGAC
AATAACTTTCCTTACTG2050
CAGTAAGGAAAGTTATT2051
Haemophilia AACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATC2052
Thr295AlaTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGACC
tACT-GCTTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCC
GGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCA2053
TCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTC
CAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGT
CTTTCCTTACTGCTCAA2054
TTGAGCAGTAAGGAAAG2055
Haemophilia ACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCT2056
Thr295lleCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGACCT
ACT-ATTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCA
TGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCC2057
ATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTT
CCAAGGACGCCTGGCGATGGTTCCTCACAAGAAATG
TTTCCTTACTGCTCAAA2058
TTTGAGCAGTAAGGAAA2059
Haemophilia ATTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGC2060
Ala296ValCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGACCTTGG
GCT-GTTACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCA
TGGTGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGG2061
TCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG
ATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAA
CCTTACTGCTCAAACAC2062
GTGTTTGAGCAGTAAGG2063
Haemophilia ATCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGA2064
Leu3O8ProCCTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCAA
CTG-CCGCATGGTAATATCTTGGATCTTTAAAATGAATATTA
TAATATTCATTTTAAAGATCCAAGATATTACCATGTTGGTGGGA2065
AGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCATCAA
GAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA
GTTTCTACTGTTTTGTC2066
GACAAAACAGTAGAAAC2067
Haemophilia AACAGCCTAATATAGCAAGACACTCTGACATTGTTTGGTTTGTC2068
Glu321LysTGACTCCAGATGGCATGGAAGCTTATGTCAAAGTAGACAGCT
gGAA-AAAGTCCAGAGGAACCCCAACTACGAATGAAAAATAATG
CATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGACAGCTGTC2069
TACTTTGACATAAGCTTCCATGCCATCTGGAGTCAGACAAACC
AAACAATGTCAGAGTGTCTTGCTATATTAGGCTGT
ATGGCATGGAAGCTTAT2070
ATAAGCTTCCATGCCAT2071
Haemophilia AATATAGCAAGACACTCTGACATTGTTTGGTTTGTCTGACTCCA2072
Tyr323TermGATGGCATGGAAGCTTATGTCAAAGTAGACAGCTGTCCAGAG
TATg-TAAGAACCCCAACTACGAATGAAAAATAATGAAGAAGCG
CGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGA2073
CAGCTGTCTACTTTGACATAAGCTTCCATGCCATCTGGAGTCA
GACAAACCAAACAATGTCAGAGTGTCTTGCTATAT
GAAGCTTATGTCAAAGT2074
ACTTTGACATAAGCTTC2075
Haemophilia AAAGACACTCTGACATTGTTTGGTTTGTCTGACTCCAGATGGCA2076
Val326LeuTGGAAGCTTATGTCAAAGTAGACAGCTGTCCAGAGGAACCCC
aGTA-CTAAACTACGAATGAAAAATAATGAAGAAGCGGAAGACT
AGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTC2077
CTCTGGACAGCTGTCTACTTTGACATAAGCTTCCATGCCATCT
GGAGTCAGACAAACCAAACAATGTCAGAGTGTCTT
ATGTCAAAGTAGACAGC2078
GCTGTCTACTTTGACAT2079
Haemophilia ATGACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTT2080
Cys329ArgATGTCAAAGTAGACAGCTGTCCAGAGGAACCCCAACTACGAA
cTGT-CGTTGAAAAATAATGAAGAAGCGGAAGACTATGATGATG
CATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGT2081
TGGGGTTCCTCTGGACAGCTGTCTACTTTGACATAAGCTTCC
ATGCCATCTGGAGTCAGACAAACCAAACAATGTCA
TAGACAGCTGTCCAGAG2082
CTCTGGACAGCTGTCTA2083
Haemophilia AGACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTTA2084
Cys329TyrTGTCAAAGTAGACAGCTGTCCAGAGGAACCCCAACTACGAAT
TGT-TATGAAAAATAATGAAGAAGCGGAAGACTATGATGATGA
TCATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAG2085
TTGGGGTTCCTCTGGACAGCTGTCTACTTTGACATAAGCTTCC
ATGCCATCTGGAGTCAGACAAACCAAACAATGTC
AGACAGCTGTCCAGAGG2086
CCTCTGGACAGCTGTCT2087
Haemophilia AACTCCAGATGGCATGGAAGCTTATGTCAAAGTAGACAGCTGT2088
Arg336TermCCAGAGGAACCCCAACTACGAATGAAAAATAATGAAGAAGCG
aCGA-TGAGAAGACTATGATGATGATCTTACTGATTCTGAAATGG
CCATTTCAGAATCAGTAAGATCATCATCATAGTCTTCCGCTTC2089
TTCATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGACAGCTG
TCTACTTTGACATAAGCTTCCATGCCATCTGGAGT
CCCAACTACGAATGAAA2090
TTTCATTCGTAGTTGGG2091
Haemophilia AGATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTC2092
Arg372CysCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAA
tCGC-TGCAACTTGGGTACATTACATTGCTGCTGAAGAGGAGG
CCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGATG2093
CTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGGAGAGTT
GTCATCATCAAACCTGACCACATCCATTTCAGAATC
TCCAAATTCGCTCAGTT2094
AACTGAGCGAATTTGGA2095
Haemophilia AATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCC2096
Arg372HisTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAA
CGC-CACACTTGGGTACATTACATTGCTGCTGAAGAGGAGGA
TCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGAT2097
GCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGGAGAGT
TGTCATCATCAAACCTGACCACATCCATTTCAGAAT
CCAAATTCGCTCAGTTG2098
CAACTGAGCGAATTTGG2099
Haemophilia ACTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC2100
Ser373LeuCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACT
TCA-TTATGGGTACATTACATTGCTGCTGAAGAGGAGGACTG
CAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG2101
GATGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGGAG
AGTTGTCATCATCAAACCTGACCACATCCATTTCAG
AATTCGCTCAGTTGCCA2102
TGGCAACTGAGCGAATT2103
Haemophilia ATCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTT2104
Ser373ProCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAAC
cTCA-CCATTGGGTACATTACATTGCTGCTGAAGAGGAGGACT
AGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGG2105
ATGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGGAGA
GTTGTCATCATCAAACCTGACCACATCCATTTCAGA
AAATTCGCTCAGTTGCC2106
GGCAACTGAGCGAATTT2107
Haemophilia ACTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC2108
Ser373TermCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACT
TCA-TAATGGGTACATTACATTGCTGCTGAAGAGGAGGACTG
CAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG2109
GATGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGGAG
AGTTGTCATCATCAAACCTGACCACATCCATTTCAG
AATTCGCTCAGTTGCCA2110
TGGCAACTGAGCGAATT2111
Haemophilia ACCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTA2112
lle386PheAAACTTGGGTACATTACATTGCTGCTGAAGAGGAGGACTGGG
cATT-TTTACTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGT
ACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCAG2113
TCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGAT
GCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGG
TACATTACATTGCTGCT2114
AGCAGCAATGTAATGTA2115
Haemophilia ACTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAA2116
lle386SerAACTTGGGTACATTACATTGCTGCTGAAGAGGAGGACTGGGA
ATT-AGTCTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGTA
TACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCA2117
GTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGA
TGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAG
ACATTACATTGCTGCTG2118
CAGCAGCAATGTAATGT2119
Haemophilia AAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACA2120
Glu390GlyTTACATTGCTGCTGAAGAGGAGGACTGGGACTATGCTCCCTT
GAG-GGGAGTCCTCGCCCCCGATGACAGGTAAGCACTTTTTGA
TCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGACTAAGGGA2121
GCATAGTCCCAGTCCTCCTCTTCAGCAGCAATGTAATGTACC
CAAGTTTTAGGATGCTTCTTGGCAACTGAGCGAATTT
TGCTGAAGAGGAGGACT2122
AGTCCTCCTCTTCAGCA2123
Haemophilia ATCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACATTACATTG2124
Trp393GlyCTGCTGAAGAGGAGGACTGGGACTATGCTCCCTTAGTCCTCG
cTGG-GGGCCCCCGATGACAGGTAAGCACTTTTTGACTATTGGT
ACCAATAGTCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGA2125
CTAAGGGAGCATAGTCCCAGTCCTCCTCTTCAGCAGCAATGT
AATGTACCCAAGTTTTAGGATGCTTCTTGGCAACTGA
AGGAGGACTGGGACTAT2126
ATAGTCCCAGTCCTCCT2127
Haemophilia AGCCTACCTAGAATTTTTCTTCCCAACCTCTCATCTTTTTTTCTC2128
Lys408lleTTATACAGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTC
AAA-ATAAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATT
AATCGGACTTTTTTGTACTTCCTACCAATCCGCTGAGGGCCAT2129
TGTTCAAATATTGACTTTTATAACTTCTGTATAAGAGAAAAAAA
GATGAGAGGTTGGGAAGAAAAATTCTAGGTAGGC
AAGTTATAAAAGTCAAT2130
ATTGACTTTTATAACTT2131
Haemophilia ATTTTCTTCCCAACCTCTCATCTTTTTTTCTCTTATACAGAAGTT2132
Leu412PheATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTAG
TTGa-TTTGAAGTACAAAAAAGTCCGATTTATGGCATACACA
TGTGTATGCCATAAATCGGACTTTTTTGTACTTCCTACCAATC2133
CGCTGAGGGCCATTGTTCAAATATTGACTTTTATAACTTCTGT
ATAAGAGAAAAAAAGATGAGAGGTTGGGAAGAAAA
CAATATTTGAACAATGG2134
CCATTGTTCAAATATTG2135
Haemophilia ATCATCTTTTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTG2136
Arg418TrpAACAATGGCCCTCAGCGGATTGGTAGGAAGTACAAAAAAGTC
gCGG-TGGCGATTTATGGCATACACAGATGAAACCTTTAAGA
TCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGACTTTTTTG2137
TACTTCCTACCAATCCGCTGAGGGCCATTGTTCAAATATTGAC
TTTTATAACTTCTGTATAAGAGAAAAAAAGATGA
GCCCTCAGCGGATTGGT2138
ACCAATCCGCTGAGGGC2139
Haemophilia ATTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTGAACAAT2140
Gly420ValGGCCCTCAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATTT
GGT-GTTATGGCATACACAGATGAAACCTTTAAGACTCGTGA
TCACGAGTCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGA2141
CTTTTTTGTACTTCCTACCAATCCGCTGAGGGCCATTGTTCAA
ATATTGACTTTTATAACTTCTGTATAAGAGAAAAA
GCGGATTGGTAGGAAGT2142
ACTTCCTACCAATCCGC2143
Haemophilia AGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGAT2144
Lys425ArgTGGTAGGAAGTACAAAAAAGTCCGATTTATGGCATACACAGAT
AAA-AGAGAAACCTTTAAGACTCGTGAAGCTATTCAGCATGA
TCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT2145
ATGCCATAAATCGGACTTTTTTGTACTTCCTACCAATCCGCTG
AGGGCCATTGTTCAAATATTGACTTTTATAACTTC
GTACAAAAAAGTCCGAT2146
ATCGGACTTTTTTGTAC2147
Haemophilia ATATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTA2148
Arg427TermGGAAGTACAAAAAAGTCCGATTTATGGCATACACAGATGAAAC
cCGA-TGACTTTAAGACTCGTGAAGCTATTCAGCATGAATCAG
CTGATTCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATC2149
TGTGTATGCCATAAATCGGACTTTTTTGTACTTCCTACCAATC
CGCTGAGGGCCATTGTTCAAATATTGACTTTTATA
AAAAAGTCCGATTTATG2150
CATAAATCGGACTTTTT2151
Haemophilia ATATTTGAACAATGGCCCTCAGCGGATTGGTAGGAAGTACAAA2152
Tyr431AsnAAAGTCCGATTTATGGCATACACAGATGAAACCTTTAAGACTC
aTAC-AACGTGAAGCTATTCAGCATGAATCAGGAATCTTGGGAC
GTCCCAAGATTCCTGATTCATGCTGAATAGCTTCACGAGTCTT2153
AAAGGTTTCATCTGTGTATGCCATAAATCGGACTTTTTTGTAC
TTCCTACCAATCCGCTGAGGGCCATTGTTCAAATA
TTATGGCATACACAGAT2154
ATCTGTGTATGCCATAA2155
Haemophilia AGCCCTCAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATTTA2156
Thr435lleTGGCATACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCA
ACC-ATCGCATGAATCAGGAATCTTGGGACCTTTACTTTATGG
CCATAAAGTAAAGGTCCCAAGATTCCTGATTCATGCTGAATAG2157
CTTCACGAGTCTTAAAGGTTTCATCTGTGTATGCCATAAATCG
GACTTTTTTGTACTTCCTACCAATCCGCTGAGGGC
AGATGAAACCTTTAAGA2158
TCTTAAAGGTTTCATCT2159
Haemophilia AACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATGA2160
Pro451LeuATCAGGAATCTTGGGACCTTTACTTTATGGGGAAGTTGGAGA
CCT-CTTCACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGTC
GACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAA2161
CTTCCCCATAAAGTAAAGGTCCCAAGATTCCTGATTCATGCTG
AATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT
CTTGGGACCTTTACTTT2162
AAAGTAAAGGTCCCAAG2163
Haemophilia ATACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATG2164
Pro451ThrAATCAGGAATCTTGGGACCTTTACTTTATGGGGAAGTTGGAGA
aCCT-ACTCACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGT
ACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAACT2165
TCCCCATAAAGTAAAGGTCCCAAGATTCCTGATTCATGCTGAA
TAGCTTCACGAGTCTTAAAGGTTTCATCTGTGTA
TCTTGGGACCTTTACTT2166
AAGTAAAGGTCCCAAGA2167
Haemophilia AACCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCT2168
Gly455ArgTGGGACCTTTACTTTATGGGGAAGTTGGAGACACACTGTTGG
tGGG-AGGTAAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGA
TCTTCTTACCTGACCTTAAATCTTTTTCTTCAACTTACCAACAGT2169
GTGTCTCCAACTTCCCCATAAAGTAAAGGTCCCAAGATTCCTG
ATTCATGCTGAATAGCTTCACGAGTCTTAAAGGT
TACTTTATGGGGAAGTT2170
AACTTCCCCATAAAGTA2171
Haemophilia ACCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCTT2172
Gly455GluGGGACCTTTACTTTATGGGGAAGTTGGAGACACACTGTTGGT
GGG-GAGAAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGAA
TTCTTCTTACCTGACCTTAAATCTTTTCTTCAACTTACCAACAG2173
TGTGTCTCCAACTTCCCCATAAAGTAAAGGTCCCAAGATTCCT
GATTCATGCTGAATAGCTTCACGAGTCTTAAAGG
ACTTTATGGGGAAGTTG2174
CAACTTCCCCATAAAGT2175
Haemophilia ACGTGAAGCTATTCAGCATGAATCAGGAATCTTGGGACCTTTAC2176
Asp459AsnTTTATGGGGAAGTTGGAGACACACTGTTGGTAAGTTGAAGAA
aGAC-AACAAGATTTAAGGTCAGGTAAGAAGAAAAAGTCTGGAG
CTCCAGACTTTTTCTTCTTACCTGACCTTAAATCTTTTCTTCAA2177
CTTACCAACAGTGTGTCTCCAACTTCCCCATAAAGTAAAGGTC
CCAAGATTCCTGATTCATGCTGAATAGCTTCACG
AAGTTGGAGACACACTG2178
CAGTGTGTCTCCAACTT2179
Haemophilia ATGTTGATCCTAGTCGTTTTAGGATTTGATCTTAGATCTCGCTTA2180
Phe465CysTACTTTCAGATTATATTTAAGAATCAAGCAAGCAGACCATATAA
TTT-TGTCATCTACCCTCACGGAATCACTGATGTCCGTCC
GGACGGACATCAGTGATTCCGTGAGGGTAGATGTTATATGGT2181
CTGCTTGCTTGATTCTTAAATATAATCTGAAAGTATAAGCGAG
ATCTAAGATCAAATCCTAAAACGACTAGGATCAACA
GATTATATTTAAGAATC2182
GATTCTTAAATATAATC2183
Haemophilia ATCGTTTTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATT2184
Ala469GlyATATTTAAGAATCAAGCAAGCAGACCATATAACATCTACCCTC
GCA-GGAACGGAATCACTGATGTCCGTCCTTTGTATTCAAG
CTTGAATACAAAGGACGGACATCAGTGATTCCGTGAGGGTAG2185
ATGTTATATGGTCTGCTTGCTTGATTCTTAAATATAATCTGAAA
GTATAAGCGAGATCTAAGATCAAATCCTAAAACGA
GAATCAAGCAAGCAGAC2186
GTCTGCTTGCTTGATTC2187
Haemophilia ATTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATTATATT2188
Arg471GlyTAAGAATCAAGCAAGCAGACCATATAACATCTACCCTCACGG
cAGA-GGAAATCACTGATGTCCGTCCTTTGTATTCAAGGAGAT
ATCTCCTTGAATACAAAGGACGGACATCAGTGATTCCGTGAG2189
GGTAGATGTTATATGGTCTGCTTGCTTGATTCTTAAATATAATC
TGAAAGTATAAGCGAGATCTAAGATCAAATCCTAA
AAGCAAGCAGACCATAT2190
ATATGGTCTGCTTGCTT2191
Haemophilia ATTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAAT2192
Tyr473CysCAAGCAAGCAGACCATATAACATCTACCCTCACGGAATCACT
TAT-TGTGATGTCCGTCCTTTGTATTCAAGGAGATTACCAAA
TTTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTC2193
CGTGAGGGTAGATGTTATATGGTCTGCTTGCTTGATTCTTAAA
TATAATCTGAAAGTATAAGCGAGATCTAAGATCAA
CAGACCATATAACATCT2194
AGATGTTATATGGTCTG2195
Haemophilia ATTTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAA2196
Tyr473HisTCAAGCAAGCAGACCATATAACATCTACCCTCACGGAATCACT
aTAT-CATGATGTCCGTCCTTTGTATTCAAGGAGATTACCAA
TTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTCC2197
GTGAGGGTAGATGTTATATGGTCTGCTTGCTTGATTCTTAAAT
ATAATCTGAAAGTATAAGCGAGATCTAAGATCAAA
GCAGACCATATAACATC2198
GATGTTATATGGTCTGC2199
Haemophilia ATTAGATCTCGCTTATACTTTCAGATTATATTTAAGAATCAAGCA2200
lle475ThrAGCAGACCATATAACATCTACCCTCACGGAATCACTGATGTCC
ATC-ACCGTCCTTTGTATTCAAGGAGATTACCAAAAGGTAA
TTACCTTTTGGTAATCTCCTTGAATACAAAGGACGGACATCAG2201
TGATTCCGTGAGGGTAGATGTTATATGGTCTGCTTGCTTGATT
CTTAAATATAATCTGAAAGTATAAGCGAGATCTAA
ATATAACATCTACCCTC2202
GAGGGTAGATGTTATAT2203
Haemophilia ATTATACTTTCAGATTATATTTAAGAATCAAGCAAGCAGACCATA2204
Gly479ArgTAACATCTACCCTCACGGAATCACTGATGTCCGTCCTTTGTAT
cGGA-AGATCAAGGAGATTACCAAAAGGTAAATATTCCCTCG
CGAGGGAATATTTACCTTTTGGTAATCTCCTTGAATACAAAGG2205
ACGGACATCAGTGATTCCGTGAGGGTAGATGTTATATGGTCT
GCTTGCTTGATTCTTAAATATAATCTGAAAGTATAA
ACCCTCACGGAATCACT2206
AGTGATTCCGTGAGGGT2207
Haemophilia ACCAATTCTGCCAGGAGAAATATTCAAATATAAATGGACAGTGA2208
Thr522SerCTGTAGAAGATGGGCCAACTAAATCAGATCCTCGGTGCCTGA
aACT-TCTCCCGCTATTACTCTAGTTTCGTTAATATGGAGAGAG
CTCTCTCCATATTAACGAAACTAGAGTAATAGCGGGTCAGGC2209
ACCGAGGATCTGATTTAGTTGGCCCATCTTCTACAGTCACTGT
CCATTTATATTTGAATATTTCTCCTGGCAGAATTGG
ATGGGCCAACTAAATCA2210
TGATTTAGTTGGCCCAT2211
Haemophilia ACCAGGAGAAATATTCAAATATAAATGGACAGTGACTGTAGAAG2212
Asp525AsnATGGGCCAACTAAATCAGATCCTCGGTGCCTGACCCGCTATT
aGAT-AATACTCTAGTTTCGTTAATATGGAGAGAGATCTAGCTT
AAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTAATAGCG2213
GGTCAGGCACCGAGGATCTGATTTAGTTGGCCCATCTTCTAC
AGTCACTGTCCATTTATATTTGAATATTTCTCCTGG
CTAAATCAGATCCTCGG2214
CCGAGGATCTGATTTAG2215
Haemophilia AGAAATATTCAAATATAAATGGACAGTGACTGTAGAAGATGGGC2216
Arg527TrpCAACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTA
tCGG-TGGGTTTCGTTAATATGGAGAGAGATCTAGCTTCAGGAC
GTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTA2217
ATAGCGGGTCAGGCACCGAGGATCTGATTTAGTTGGCCCATC
TTCTACAGTCACTGTCCATTTATATTTGAATATTTC
CAGATCCTCGGTGCCTG2218
CAGGCACCGAGGATCTG2219
Haemophilia ATATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA2220
Arg531CysGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTTCGTTAATA
cCGC-TGCTGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTC
GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA2221
CGAAACTAGAGTAATAGCGGGTCAGGCACCGAGGATCTGATT
TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA
GCCTGACCCGCTATTAC2222
GTAATAGCGGGTCAGGC2223
Haemophilia ATATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA2224
Arg531GlyGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTTCGTTAATA
cCGC-GGCTGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTC
GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA2225
CGAAACTAGAGTAATAGCGGGTCAGGCACCGAGGATCTGATT
TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA
GCCTGACCCGCTATTAC2226
GTAATAGCGGGTCAGGC2227
Haemophilia AATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCAG2228
Arg531HisATCCTCGGTGCCTGACCCGCTATTACTCTAGTTTCGTTAATAT
CGC-CACGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCT
AGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA2229
CGAAACTAGAGTAATAGCGGGTCAGGCACCGAGGATCTGATT
TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTAT
CCTGACCCGCTATTACT2230
AGTAATAGCGGGTCAGG2231
Haemophilia AACAGTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGG2232
Ser534ProTGCCTGACCCGCTATTACTCTAGTTTCGTTAATATGGAGAGAG
cTCT-CCTATCTAGCTTCAGGACTCATTGGCCCTCTCCTCATCT
AGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCT2233
CCATATTAACGAAACTAGAGTAATAGCGGGTCAGGCACCGAG
GATCTGATTTAGTTGGCCCATCTTCTACAGTCACTGT
GCTATTACTCTAGTTTC2234
GAAACTAGAGTAATAGC2235
Haemophilia AGTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGGTGC2236
Ser535GlyCTGACCCGCTATTACTCTAGTTTCGTTAATATGGAGAGAGATC
tAGT-GGTTAGCTTCAGGACTCATTGGCCCTCTCCTCATCTGCT
AGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTC2237
TCTCCATATTAACGAAACTAGAGTAATAGCGGGTCAGGCACC
GAGGATCTGATTTAGTTGGCCCATCTTCTACAGTCAC
ATTACTCTAGTTTCGTT2238
AACGAAACTAGAGTAAT2239
Haemophilia ATAGAAGATGGGCCAACTAAATCAGATCCTCGGTGCCTGACCC2240
Val537AspGCTATTACTCTAGTTTCGTTAATATGGAGAGAGATCTAGCTTC
GTT-GATAGGACTCATTGGCCCTCTCCTCATCTGCTACAAAGA
TCTTTGTAGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCT2241
AGATCTCTCTCCATATTAACGAAACTAGAGTAATAGCGGGTCA
GGCACCGAGGATCTGATTTAGTTGGCCCATCTTCTA
TAGTTTCGTTAATATGG2242
CCATATTAACGAAACTA2243
Haemophilia ACAACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTA2244
Arg541ThrGTTTCGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGG
AGA-ACACCCTCTCCTCATCTGCTACAAAGAATCTGTAGATCA
TGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAATG2245
AGTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAGT
AATAGCGGGTCAGGCACCGAGGATCTGATTTAGTTG
TATGGAGAGAGATCTAG2246
CTAGATCTCTCTCCATA2247
Haemophilia ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTT2248
Asp542GlyCGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCC
GAT-GGTTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAAG
CTTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCA2249
ATGAGTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAG
AGTAATAGCGGGTCAGGCACCGAGGATCTGATTTAG
GGAGAGAGATCTAGCTT2250
AAGCTAGATCTCTCTCC2251
Haemophilia AACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT2252
Asp542HisTCGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCC
aGAT-CATCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAA
TTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAAT2253
GAGTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAG
TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT
TGGAGAGAGATCTAGCT2254
AGCTAGATCTCTCTCCA2255
Haemophilia AACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT2256
Asp542TyrTCGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCC
aGAT-TATCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAA
TTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAAT2257
GAGTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAG
TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT
TGGAGAGAGATCTAGCT2258
AGCTAGATCTCTCTCCA2259
Haemophilia AGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCT2260
Glu557TermCTCCTCATCTGCTACAAAGAATCTGTAGATCAAAGAGGAAACC
aGAA-TAAAGGTGAGTTCTTGCCTTTCCAAGTGCTGGGTTTCAT
ATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGGTTTC2261
CTCTTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGC
CAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAAC
GCTACAAAGAATCTGTA2262
TACAGATTCTTTGTAGC2263
Haemophilia AATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCC2264
Ser558PheTCATCTGCTACAAAGAATCTGTAGATCAAAGAGGAAACCAGGT
TCT-TTTGAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTC
GAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGG2265
TTTCCTCTTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAG
GGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATAT
CAAAGAATCTGTAGATC2266
GATCTACAGATTCTTTG2267
Haemophilia ATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCCTCA2268
Val559AlaTCTGCTACAAAGAATCTGTAGATCAAAGAGGAAACCAGGTGA
GTA-GCAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTCAGT
ACTGAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACC2269
TGGTTTCCTCTTTGATCTACAGATTCTTTGTAGCAGATGAGGA
GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCA
AGAATCTGTAGATCAAA2270
TTTGATCTACAGATTCT2271
|
Hemophilia—Factor IX Deficiency
[0139] The attached table discloses the correcting oligonucleotide base sequences for the Factor IX oligonucleotides of the invention.
22TABLE 21
|
|
Factor IX Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Haemophilia BATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA2272
|
Asn2AspTCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTT
|
tAAT-GATCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAA
|
TTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT2273
|
TCCAATTTACCTGAATTATACCTCTTTGGCCGATTCAGAATTTT
|
GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT
|
AGAGGTATAATTCAGGT2274
|
ACCTGAATTATACCTCT2275
|
Haemophilia BTTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAAT2276
|
Asn2IleCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTT
|
AAT-ATTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAA
|
TTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTC2277
|
TTCCAATTTACCTGAATTATACCTCTTTGGCCGATTCAGAATTT
|
TGTTGGCGTTTTCATGATCAAGAAAAACTGAAA
|
GAGGTATAATTCAGGTA2278
|
TACCTGAATTATACCTC2279
|
Haemophilia BATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA2280
|
Asn2TyrTCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTT
|
tAAT-TATCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAA
|
TTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT2281
|
TCCAATTTACCTGAATTATACCTCTTTGGCCGATTCAGAATTTT
|
GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT
|
AGAGGTATAATTCAGGT2282
|
ACCTGAATTATACCTCT2283
|
Haemophilia BTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATC2284
|
Ser3ProGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCA
|
tTCA-CCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT
|
ACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAAC2285
|
TCTTCCAATTTACCTGAATTATACCTCTTTGGCCGATTCAGAA
|
TTTTGTTGGCGTTTTCATGATCAAGAAAAACTGA
|
GGTATAATTCAGGTAAA2286
|
TTTACCTGAATTATACC2287
|
Haemophilia BTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCC2288
|
Gly4AspAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGG
|
GGT-GATAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAG
|
CTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC2289
|
AAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCGATTCA
|
GAATTTTGTTGGCGTTTTCATGATCAAGAAAAA
|
TAATTCAGGTAAATTGG2290
|
CCAATTTACCTGAATTA2291
|
Haemophilia BGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGC2292
|
Gly4SerCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGG
|
aGGT-AGTGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTA
|
TACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACA2293
|
AACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCGATTCA
|
GAATTTTGTTGGCGTTTTCATGATCAAGAAAAAC
|
ATAATTCAGGTAAATTG2294
|
CAATTTACCTGAATTAT2295
|
Haemophilia BTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAA2296
|
Lys5GluAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAA
|
tAAA-GAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTT
|
AACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGA2297
|
ACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCGATT
|
CAGAATTTTGTTGGCGTTTTCATGATCAAGAAA
|
ATTCAGGTAAATTGGAA2298
|
TTCCAATTTACCTGAAT2299
|
Haemophilia BATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA2300
|
Glu7AlaTAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAG
|
GAA-GCAAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGA
|
TCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT2301
|
CCCTTGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTG
|
GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT
|
TAAATTGGAAGAGTTTG2302
|
CAAACTCTTCCAATTTA2303
|
Haemophilia BGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGG2304
|
Glu7LysTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTG
|
gGAA-AAAAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAG
|
CTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTC2305
|
CCTTGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGG
|
CCGATTCAGAATTTTGTTGGCGTTTTCATGATC
|
GTAAATTGGAAGAGTTT2306
|
AAACTCTTCCAATTTAC2307
|
Haemophilia BATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA2308
|
Glu7ValTAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAG
|
GAA-GTAAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGA
|
TCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT2309
|
CCCTTGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTG
|
GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT
|
TAAATTGGAAGAGTTTG2310
|
CAAACTCTTCCAATTTA2311
|
Haemophilia BATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA2312
|
Glu8AlaTTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAG
|
GAG-GCGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGC
|
GCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG2313
|
GTTCCCTTGAACAAACTCTTCCAATTTACCTGAATTATACCTCT
|
TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT
|
ATTGGAAGAGTTTGTTC2314
|
GAACAAACTCTTCCAAT2315
|
Haemophilia BATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA2316
|
Glu8GlyTTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAG
|
GAG-GGGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGC
|
GCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG2317
|
GTTCCCTTGAACAAACTCTTCCAATTTACCTGAATTATACCTCT
|
TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT
|
ATTGGAAGAGTTTGTTC2318
|
GAACAAACTCTTCCAAT2319
|
Haemophilia BAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTC2320
|
Phe9CysAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGA
|
TTT-TGTATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACG
|
CGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTC2321
|
AAGGTTCCCTTGAACAAACTCTTCCAATTTACCTGAATTATAC
|
CTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTT
|
GGAAGAGTTTGTTCAAG2322
|
CTTGAACAAACTCTTCC2323
|
Haemophilia BGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATT2324
|
Phe9IleCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG
|
gTTT-ATTAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCAC
|
GTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCA2325
|
AGGTTCCCTTGAACAAACTCTTCCAATTTACCTGAATTATACC
|
TCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTC
|
TGGAAGAGTTTGTTCAA2326
|
TTGAACAAACTCTTCCA2327
|
Haemophilia BTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTC2328
|
Arg(−1)SerTGAATCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTT
|
AGGt-AGCTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAA
|
TTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCC2329
|
AATTTACCTGAATTATACCTCTTTGGCCGATTCAGAATTTTGTT
|
GGCGTTTTCATGATCAAGAAAAACTGAAATGTAA
|
CCAAAGAGGTATAATTC2330
|
GAATTATACCTCTTTGG2331
|
Haemophilia BTTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATT2332
|
Arg(−1)ThrCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAG
|
AGG-ACGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGA
|
TCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCA2333
|
ATTTACCTGAATTATACCTCTTTGGCCGATTCAGAATTTTGTTG
|
GCGTTTTCATGATCAAGAAAAACTGAAATGTAAA
|
GCCAAAGAGGTATAATT2334
|
AATTATACCTCTTTGGC2335
|
Haemophilia BCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAA2336
|
Lys(−2)AsnTTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGA
|
AAGa-AATGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATG
|
CATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAAT2337
|
TTACCTGAATTATACCTCTTTGGCCGATTCAGAATTTTGTTGG
|
CGTTTTCATGATCAAGAAAAACTGAAATGTAAAAG
|
CGGCCAAAGAGGTATAA2338
|
TTATACCTCTTTGGCCG2339
|
Haemophilia BAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC2340
|
Arg(−4)GlnAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAAT
|
CGG-CAGTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGA
|
TCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG2341
|
AATTATACCTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTCA
|
TGATCAAGAAAAACTGAAATGTAAAAGAATAATT
|
TCTGAATCGGCCAAAGA2342
|
TCTTTGGCCGATTCAGA2343
|
Haemophilia BAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC2344
|
Arg(−4)LeuAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAAT
|
CGG-CTGTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGA
|
TCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG2345
|
AATTATACCTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTCA
|
TGATCAAGAAAAACTGAAATGTAAAAGAATAATT
|
TCTGAATCGGCCAAAGA2346
|
TCTTTGGCCGATTCAGA2347
|
Haemophilia BGAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGC2348
|
Arg(−4)TrpCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAA
|
tCGG-TGGTTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG
|
CTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTGA2349
|
ATTATACCTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT
|
GATCAAGAAAAACTGAAATGTAAAAGAATAATTC
|
TTCTGAATCGGCCAAAG2350
|
CTTTGGCCGATTCAGAA2351
|
Haemophilia BGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTA2352
|
Gin11TermAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTAT
|
tCAA-TAAGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAG
|
CTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCT 2353
|
CTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTGAAT
|
TATACCTCTTTGGCCGATTCAGAATTTTGTTGGC
|
AGTTTGTTCAAGGGAAC2354
|
GTTCCCTTGAACAAACT2355
|
Haemophilia BACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT2356
|
Gly12AlaGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGA
|
GGG-GCGAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTT
|
AAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA2357
|
TTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCT
|
GAATTATACCTCTTTGGCCGATTCAGAATTTTGT
|
TGTTCAAGGGAACCTTG2358
|
CAAGGTTCCCTTGAACA2359
|
Haemophilia BAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAAT2360
|
Gly12ArgTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGG
|
aGGG-AGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTT
|
AAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACAT2361
|
TCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG
|
AATTATACCTCTTTGGCCGATTCAGAATTTTGTT
|
TTGTTCAAGGGAACCTT2362
|
AAGGTTCCCTTGAACAA2363
|
Haemophilia BACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT2364
|
Gly12GluGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGA
|
GGG-GAGAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTT
|
AAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA2365
|
TTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCT
|
GAATTATACCTCTTTGGCCGATTCAGAATTTTGT
|
TGTTCAAGGGAACCTTG2366
|
CAAGGTTCCCTTGAACA2367
|
Haemophilia BCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC2368
|
Glu17GlnAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTT
|
aGAA-CAATTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAA
|
TTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC2369
|
TTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTC
|
TTCCAATTTACCTGAATTATACCTCTTTGGCCG
|
TTGAGAGAGAATGTATG2370
|
CATACATTCTCTCTCAA2371
|
Haemophilia BCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC2372
|
Glu17LysAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTT
|
aGAA-AAATTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAA
|
TTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC2373
|
TTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTC
|
TTCCAATTTACCTGAATTATACCTCTTTGGCCG
|
TTGAGAGAGAATGTATG2374
|
CATACATTCTCTCTCAA2375
|
Haemophilia BCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAG2376
|
Cys18ArgGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTG
|
aTGT-CGTAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAA
|
TTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTA2377
|
CACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAA
|
ACTCTTCCAATTTACCTGAATTATACCTCTTTGG
|
AGAGAGAATGTATGGAA2378
|
TTCCATACATTCTCTCT2379
|
Haemophilia BCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGG2380
|
Cys18TyrGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAA
|
TGT-TATGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAAC
|
GTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACT2381
|
ACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAA
|
ACTCTTCCAATTTACCTGAATTATACCTCTTTG
|
GAGAGAATGTATGGAAG2382
|
CTTCCATACATTCTCTC2383
|
Haemophilia BGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCT2384
|
Glu20ValTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGC
|
GAA-GTAACGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAG
|
CTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTC2385
|
AAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTT
|
GAACAAACTCTTCCAATTTACCTGAATTATACC
|
ATGTATGGAAGAAAAGT2386
|
ACTTTTCTTCCATACAT2387
|
Haemophilia BTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTG2388
|
Glu21LysAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCAC
|
aGAA-AAAGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAGTA
|
TACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCT2389
|
TCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCC
|
TTGAACAAACTCTTCCAATTTACCTGAATTATA
|
GTATGGAAGAAAAGTGT2390
|
ACACTTTTCTTCCATAC2391
|
Haemophilia BTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGA2392
|
Cys23ArgGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAA
|
gTGT-CGTGTTTTTGAAAACACTGAAAGAACAGTGAGTATTTCCA
|
TGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGT2393
|
GCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG
|
GTTCCCTTGAACAAACTCTTCCAATTTACCTGA
|
AAGAAAAGTGTAGTTTT2394
|
AAAACTACACTTTTCTT2395
|
Haemophilia BCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG2396
|
Cys23TyrAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGT
|
TGT-TATTTTTGAAAACACTGAAAGAACAGTGAGTATTTCCAC
|
GTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTC2397
|
GTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCA
|
AGGTTCCCTTGAACAAACTCTTCCAATTTACCTG
|
AGAAAAGTGTAGTTTTG2398
|
CAAAACTACACTTTTCT2399
|
Haemophilia BAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTAT2400
|
Phe25SerGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAA
|
TTT-TCTAACACTGAAAGAACAGTGAGTATTTCCACATAATA
|
TATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAAC2401
|
TTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTC
|
TCTCAAGGTTCCCTTGAACAAACTCTTCCAATT
|
GTGTAGTTTTGAAGAAG2402
|
CTTCTTCAAAACTACAC2403
|
Haemophilia BTTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATG2404
|
Glu26GlnGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAA
|
tGAA-CAAACACTGAAAGAACAGTGAGTATTTCCACATAATACC
|
GGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAA2405
|
ACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTC
|
TCTCTCAAGGTTCCCTTGAACAAACTCTTCCAA
|
GTAGTTTTGAAGAAGCA2406
|
TGCTTCTTCAAAACTAC2407
|
Haemophilia BAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAG2408
|
Glu27AlaAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACAC
|
GAA-GCATGAAAGAACAGTGAGTATTTCCACATAATACCCTTC
|
GAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT2409
|
CAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATA
|
CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT
|
TTTTGAAGAAGCACGAG2410
|
CTCGTGCTTCTTCAAAA2411
|
Haemophilia BAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGA2412
|
Glu27AspAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACT
|
GAAg-GACGAAAGAACAGTGAGTATTTCCACATAATACCCTTCA
|
TGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTT2413
|
TCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCAT
|
ACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT
|
TTTGAAGAAGCACGAGA2414
|
TCTCGTGCTTCTTCAAA2415
|
Haemophilia BGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAA2416
|
Glu27LysGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACA
|
aGAA-AAACTGAAAGAACAGTGAGTATTTCCACATAATACCCTT
|
AAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTC2417
|
AAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATAC
|
ATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTC
|
GTTTTGAAGAAGCACGA2418
|
TCGTGCTTCTTCAAAAC2419
|
Haemophilia BAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAG2420
|
Glu27ValAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACAC
|
GAA-GTATGAAAGAACAGTGAGTATTTCCACATAATACCCTTC
|
GAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT2421
|
CAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATA
|
CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT
|
TTTTGAAGAAGCACGAG2422
|
CTCGTGCTTCTTCAAAA2423
|
Haemophilia BTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT2424
|
Arg29GlnGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAG
|
CGA-CAAAACAGTGAGTATTTCCACATAATACCCTTCAGATGC
|
GCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG2425
|
TGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCT
|
TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA
|
AGAAGCACGAGAAGTTT2426
|
AAACTTCTCGTGCTTCT2427
|
Haemophilia BTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT2428
|
Arg29ProGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAG
|
CGA-CCAAACAGTGAGTATTTCCACATAATACCCTTCAGATGC
|
GCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG2429
|
TGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCT
|
TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA
|
AGAAGCACGAGAAGTTT2430
|
AAACTTCTCGTGCTTCT2431
|
Haemophilia BTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT2432
|
Arg29TermGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAG
|
aCGA-TGAAACAGTGAGTATTTCCACATAATACCCTTCAGATG
|
CATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGT2433
|
GTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTT
|
CCATACATTCTCTCTCAAGGTTCCCTTGAACAAA
|
AAGAAGCACGAGAAGTT2434
|
AACTTCTCGTGCTTCTT2435
|
Haemophilia BGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT2436
|
Glu30LysAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAA
|
aGAA-AAACAGTGAGTATTTCCACATAATACCCTTCAGATGCAG
|
CTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC2437
|
AGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTT
|
CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC
|
AAGCACGAGAAGTTTTT2438
|
AAAAACTTCTCGTGCTT2439
|
Haemophilia BGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT2440
|
Glu30TermAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAA
|
aGAA-TAACAGTGAGTATTTCCACATAATACCCTTCAGATGCAG
|
CTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC2441
|
AGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACACTTTT
|
CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC
|
AAGCACGAGAAGTTTTT2442
|
AAAAACTTCTCGTGCTT2443
|
Haemophilia BCCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAA2444
|
Glu33AspGCACGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAGTATTT
|
CAAa-GACCCACATAATACCCTTCAGATGCAGAGCATAGAATA
|
TATTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTC2445
|
ACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAA
|
ACTACACTTTTCTTCCATACATTCTCTCTCAAGG
|
GTTTTTGAAAACACTGA2446
|
TCAGTGTTTTCAAAAAC2447
|
Haemophilia BAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAG2448
|
Glu33TermAAGCACGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAGTAT
|
tGAA-TAATTCCACATAATACCCTTCAGATGCAGAGCATAGAA
|
TTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTCAC2449
|
TGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAAC
|
TACACTTTTCTTCCATACATTCTCTCTCAAGGTT
|
AAGTTTTTGAAAACACT2450
|
AGTGTTTTCAAAAACTT2451
|
Haemophilia BCAAAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTT2452
|
Trp42TermTATAGACTGAATTTTGGAAGCAGTATGTTGGTAAGCAATTCAT
|
TGG-TAGTTTATCCTCTAGCTAATATATGAAACATATGAG
|
CTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGCTT2453
|
ACCAACATACTGCTTCCAAAATTCAGTCTATAAAGAATAAAAG
|
AAGACAAATTAACGGTAATATCTAAAGTGTTTTG
|
TGAATTTTGGAAGCAGT2454
|
ACTGCTTCCAAAATTCA2455
|
Haemophilia BAAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTA2456
|
Lys43GluTAGACTGAATTTTGGAAGCAGTATGTTGGTAAGCAATTCATTT
|
gAAG-GAGTATCCTCTAGCTAATATATGAAACATATGAGAA
|
TTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGC2457
|
TTACCAACATACTGCTTCCAAAATTCAGTCTATAAAGAATAAAA
|
GAAGACAAATTAACGGTAATATCTAAAGTGTTT
|
AATTTTGGAAGCAGTAT2458
|
ATACTGCTTCCAAAATT2459
|
Haemophilia BCACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTATAG2460
|
Gln44TermACTGAATTTTGGAAGCAGTATGTTGGTAAGCAATTCATTTTATC
|
gCAG-TAGCTCTAGCTAATATATGAAACATATGAGAATTA
|
TAATTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAAT2461
|
TGCTTACCAACATACTGCTTCCAAAATTCAGTCTATAAAGAATA
|
AAAGAAGACAAATTAACGGTAATATCTAAAGTG
|
TTTGGAAGCAGTATGTT2462
|
AACATACTGCTTCCAAA2463
|
Haemophilia BCCGGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAAC2464
|
Asp49GlyCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTA
|
GAT-GGTAATGGCGGCAGTTGCAAGGATGACATTAATTCCTA
|
TAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATG2465
|
GATTGGACTCACACTGATCTCCATCTTTGAGATAGGTTAAGAA
|
ATTGAATTGGCACGTAAACTGCTTAGAATGCCCGG
|
AGATGGAGATCAGTGTG2466
|
CACACTGATCTCCATCT2467
|
Haemophilia BGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATC2468
|
Gln50HisTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGG
|
CAGt-CACCGGCAGTTGCAAGGATGACATTAATTCCTATGAA
|
TTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAA2469
|
CATGGATTGGACTCACACTGATCTCCATCTTTGAGATAGGTTA
|
AGAAATTGAATTGGCACGTAAACTGCTTAGAATGC
|
GGAGATCAGTGTGAGTC2470
|
GACTCACACTGATCTCC2471
|
Haemophilia BGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTA2472
|
Gln50ProTCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAAT
|
CAG-CCGGGCGGCAGTTGCAAGGATGACATTAATTCCTATGA
|
TCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAAC2473
|
ATGGATTGGACTCACACTGATCTCCATCTTTGAGATAGGTTAA
|
GAAATTGAATTGGCACGTAAACTGCTTAGAATGCC
|
TGGAGATCAGTGTGAGT2474
|
ACTCACACTGATCTCCA2475
|
Haemophilia BGGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCT2476
|
Gln50TermATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAA
|
tCAG-TAGTGGCGGCAGTTGCAAGGATGACATTAATTCCTATG
|
CATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACA2477
|
TGGATTGGACTCACACTGATCTCCATCTTTGAGATAGGTTAAG
|
AAATTGAATTGGCACGTAAACTGCTTAGAATGCCC
|
ATGGAGATCAGTGTGAG2478
|
CTCACACTGATCTCCAT2479
|
Haemophilia BCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT2480
|
Cys51ArgCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGG
|
gTGT-CGTCGGCAGTTGCAAGGATGACATTAATTCCTATGAAT
|
ATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA2481
|
ACATGGATTGGACTCACACTGATCTCCATCTTTGAGATAGGTT
|
AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG
|
GAGATCAGTGTGAGTCC2482
|
GGACTCACACTGATCTC2483
|
Haemophilia BCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT2484
|
Cys51SerCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGG
|
gTGT-AGTCGGCAGTTGCAAGGATGACATTAATTCCTATGAAT
|
ATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA2485
|
ACATGGATTGGACTCACACTGATCTCCATCTTTGAGATAGGTT
|
AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG
|
GAGATCAGTGTGAGTCC2486
|
GGACTCACACTGATCTC2487
|
Haemophilia BTTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCA2488
|
Cys51TrpAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG
|
TGTg-TGGGCAGTTGCAAGGATGACATTAATTCCTATGAATGT
|
ACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTT2489
|
AAACATGGATTGGACTCACACTGATCTCCATCTTTGAGATAGG
|
TTAAGAAATTGAATTGGCACGTAAACTGCTTAGAA
|
GATCAGTGTGAGTCCAA2490
|
TTGGACTCACACTGATC2491
|
Haemophilia BTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCAA2492
|
Glu52TermAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCGG
|
tGAG-TAGCAGTTGCAAGGATGACATTAATTCCTATGAATGTT
|
AACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATT2493
|
TAAACATGGATTGGACTCACACTGATCTCCATCTTTGAGATAG
|
GTTAAGAAATTGAATTGGCACGTAAACTGCTTAGA
|
ATCAGTGTGAGTCCAAT2494
|
ATTGGACTCACACTGAT2495
|
Haemophilia BTTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG2496
|
Pro55AlaATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCA
|
tCCA-GCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCT
|
AGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT2497
|
GCCGCCATTTAAACATGGATTGGACTCACACTGATCTCCATCT
|
TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA
|
AGTCCAATCCATGTTTA2498
|
TAAACATGGATTGGACT2499
|
Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA2500
|
Pro55ArgTCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAA
|
CCA-CGAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTT
|
AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC2501
|
TGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCCATC
|
TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA
|
GTCCAATCCATGTTTAA2502
|
TTAAACATGGATTGGAC2503
|
Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA2504
|
Pro55GlnTCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAA
|
CCA-CAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTT
|
AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC2505
|
TGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCCATC
|
TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA
|
GTCCAATCCATGTTTAA2506
|
TTAAACATGGATTGGAC2507
|
Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA2508
|
Pro55LeuTCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAA
|
CCA-CTAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTT
|
AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC2509
|
TGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCCATC
|
TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA
|
GTCCAATCCATGTTTAA2510
|
TTAAACATGGATTGGAC2511
|
Haemophilia BTTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG2512
|
Pro55SerATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCA
|
tCCA-TCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCT
|
AGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT2513
|
GCCGCCATTTAAACATGGATTGGACTCACACTGATCTCCATCT
|
TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA
|
AGTCCAATCCATGTTTA2514
|
TAAACATGGATTGGACT2515
|
Haemophilia BACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC2516
|
Cys56ArgAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGG
|
aTGT-CGTATGACATTAATTCCTATGAATGTTGGTGTCCCTTTG
|
CAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA2517
|
ACTGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCC
|
ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT
|
CCAATCCATGTTTAAAT2518
|
ATTTAAACATGGATTGG2519
|
Haemophilia BACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC2520
|
Cys56SerAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGG
|
aTGT-AGTATGACATTAATTCCTATGAATGTTGGTGTCCCTTTG
|
CAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA2521
|
ACTGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCC
|
ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT
|
CCAATCCATGTTTAAAT2522
|
ATTTAAACATGGATTGG2523
|
Haemophilia BCGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA2524
|
Cys56SerGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGA
|
TGT-TCTTGACATTAATTCCTATGAATGTTGGTGTCCCTTTGG
|
CCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC2525
|
AACTGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCC
|
ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG
|
CAATCCATGTTTAAATG2526
|
CATTTAAACATGGATTG2527
|
Haemophilia BCGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA2528
|
Cys56TyrGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGA
|
TGT-TATTGACATTAATTCCTATGAATGTTGGTGTCCCTTTGG
|
CCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC2529
|
AACTGCCGCCATTTAAACATGGATTGGACTCACACTGATCTCC
|
ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG
|
CAATCCATGTTTAAATG2530
|
CATTTAAACATGGATTG2531
|
Haemophilia BATTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAG2532
|
Asn58LysTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTA
|
AATg-AAGATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAA
|
TTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCA2533
|
TCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCACACT
|
GATCTCCATCTTTGAGATAGGTTAAGAAATTGAAT
|
TGTTTAAATGGCGGCAG2534
|
CTGCCGCCATTTAAACA2535
|
Haemophilia BTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC2536
|
Gly59AspCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAAT
|
GGC-GACTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG
|
CCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT2537
|
CATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCACA
|
CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA
|
TTTAAATGGCGGCAGTT2538
|
AACTGCCGCCATTTAAA2539
|
Haemophilia BTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC2540
|
Gly59ValCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAAT
|
GGC-GTCTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG
|
CCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT2541
|
CATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCACA
|
CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA
|
TTTAAATGGCGGCAGTT2542
|
AACTGCCGCCATTTAAA2543
|
Haemophilia BTTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGT2544
|
Gly59SerCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA
|
tGGC-AGCTTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAG
|
CTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTC2545
|
ATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCACAC
|
TGATCTCCATCTTTGAGATAGGTTAAGAAATTGAA
|
GTTTAAATGGCGGCAGT2546
|
ACTGCCGCCATTTAAAC2547
|
Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA2548
|
Gly60SerATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTC
|
cGGC-AGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA
|
TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT2549
|
GTCATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCA
|
CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT
|
TAAATGGCGGCAGTTGC2550
|
GCAACTGCCGCCATTTA2551
|
Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA2552
|
Gly60CysATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTC
|
cGGC-TGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA
|
TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT2553
|
GTCATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCA
|
CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT
|
TAAATGGCGGCAGTTGC2554
|
GCAACTGCCGCCATTTA2555
|
Haemophilia BATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAA2556
|
Gly60AspTCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCC
|
GGC-GACTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAA
|
TTTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAA2557
|
TGTCATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTC
|
ACACTGATCTCCATCTTTGAGATAGGTTAAGAAAT
|
AAATGGCGGCAGTTGCA2558
|
TGCAACTGCCGCCATTT2559
|
Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA2560
|
Gly60ArgATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTC
|
cGGC-CGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA
|
TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT2561
|
GTCATCCTTGCAACTGCCGCCATTTAAACATGGATTGGACTCA
|
CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT
|
TAAATGGCGGCAGTTGC2562
|
GCAACTGCCGCCATTTA2563
|
Haemophilia BTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG2564
|
Cys62TyrTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAA
|
TGC-TACTGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTG
|
CAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG2565
|
AATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATGGATT
|
GGACTCACACTGATCTCCATCTTTGAGATAGGTTA
|
CGGCAGTTGCAAGGATG2566
|
CATCCTTGCAACTGCCG2567
|
Haemophilia BTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG2568
|
Cys62SerTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAA
|
TGC-TCCTGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTG
|
CAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG2569
|
AATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATGGATT
|
GGACTCACACTGATCTCCATCTTTGAGATAGGTTA
|
CGGCAGTTGCAAGGATG2570
|
CATCCTTGCAACTGCCG2571
|
Haemophilia BAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGT2572
|
Cys62TermTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAAT
|
TGCa-TGAGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGT
|
ACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG2573
|
GAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATGGAT
|
TGGACTCACACTGATCTCCATCTTTGAGATAGGTT
|
GGCAGTTGCAAGGATGA2574
|
TCATCCTTGCAACTGCC2575
|
Haemophilia BTCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAAT2576
|
Asp64GluGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGG
|
GATg-GAGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTA
|
TAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACAT2577
|
TCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAAC
|
ATGGATTGGACTCACACTGATCTCCATCTTTGAGA
|
TGCAAGGATGACATTAA2578
|
TTAATGTCATCCTTGCA2579
|
Haemophilia BATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAA2580
|
Asp64GlyTGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTG
|
GAT-GGTGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATT
|
AATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATT2581
|
CATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACA
|
TGGATTGGACTCACACTGATCTCCATCTTTGAGAT
|
TTGCAAGGATGACATTA2582
|
TAATGTCATCCTTGCAA2583
|
Haemophilia BTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAA2584
|
Asp64AsnATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTG
|
gGAT-AATGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAAT
|
ATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTC2585
|
ATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACAT
|
GGATTGGACTCACACTGATCTCCATCTTTGAGATA
|
GTTGCAAGGATGACATT2586
|
AATGTCATCCTTGCAAC2587
|
Haemophilia BAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG2588
|
Ile66SerGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGTGTCC
|
ATT-AGTCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAA
|
TTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC2589
|
AACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATT
|
TAAACATGGATTGGACTCACACTGATCTCCATCTT
|
GGATGACATTAATTCCT2590
|
AGGAATTAATGTCATCC2591
|
Haemophilia BAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG2592
|
Ile66ThrGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGTGTCC
|
ATT-ACTCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAA
|
TTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC2593
|
AACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATT
|
TAAACATGGATTGGACTCACACTGATCTCCATCTT
|
GGATGACATTAATTCCT2594
|
AGGAATTAATGTCATCC2595
|
Haemophilia BTGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAG2596
|
Asn67LysTTGCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTT
|
AATt-AAAGGATTTGAAGGAAAGAACTGTGAATTAGGTAAGTAA
|
TTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGAC2597
|
ACCAACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCC
|
ATTTAAACATGGATTGGACTCACACTGATCTCCA
|
GACATTAATTCCTATGA2598
|
TCATAGGAATTAATGTC2599
|
Haemophilia BATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCA2600
|
Tyr69CysAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTTGGATT
|
TAT-TGTTGAAGGAAAGAACTGTGAATTAGGTAAGTAACTATT
|
AATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAA2601
|
GGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACTG
|
CCGCCATTTAAACATGGATTGGACTCACACTGAT
|
TAATTCCTATGAATGTT2602
|
AACATTCATAGGAATTA2603
|
Haemophilia BTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGA2604
|
Cys71TermCATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGA
|
TGTt-TGAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGAA
|
TTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAA2605
|
ATCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTT
|
GCAACTGCCGCCATTTAAACATGGATTGGACTCA
|
TATGAATGTTGGTGTCC2606
|
GGACACCAACATTCATA2607
|
Haemophilia BGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG2608
|
Cys71SerACATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG
|
TGT-TCTAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGA
|
TCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA2609
|
TCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTG
|
CAACTGCCGCCATTTAAACATGGATTGGACTCAC
|
CTATGAATGTTGGTGTC2610
|
GACACCAACATTCATAG2611
|
Haemophilia BGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG2612
|
Cys71TyrACATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG
|
TGT-TATAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGA
|
TCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA2613
|
TCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTG
|
CAACTGCCGCCATTTAAACATGGATTGGACTCAC
|
CTATGAATGTTGGTGTC2614
|
GACACCAACATTCATAG2615
|
Haemophilia BTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGAT2616
|
Cys71SerGACATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAG
|
aTGT-AGTGAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTG
|
CAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAAT2617
|
CCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC
|
AACTGCCGCCATTTAAACATGGATTGGACTCACA
|
CCTATGAATGTTGGTGT2618
|
ACACCAACATTCATAGG2619
|
Haemophilia BGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGAC2620
|
Trp72ArgATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA
|
tTGG-AGGAGAACTGTGAATTAGGTAAGTAACTATTTTTTGAAT
|
ATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCA2621
|
AATCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCT
|
TGCAACTGCCGCCATTTAAACATGGATTGGACTC
|
ATGAATGTTGGTGTCCC2622
|
GGGACACCAACATTCAT2623
|
Haemophilia BGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACAT2624
|
Trp72TermTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAG
|
TGGt-TGAAACTGTGAATTAGGTAAGTAACTATTTTTTGAATAC
|
GTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTT2625
|
CAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCATC
|
CTTGCAACTGCCGCCATTTAAACATGGATTGGAC
|
GAATGTTGGTGTCCCTT2626
|
AAGGGACACCAACATTC2627
|
Haemophilia BCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA2628
|
Cys73TyrTTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAAC
|
TGT-TATTGTGAATTAGGTAAGTAACTATTTTTTGAATACTC
|
GAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC2629
|
TTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCA
|
TCCTTGCAACTGCCGCCATTTAAACATGGATTGG
|
ATGTTGGTGTCCCTTTG2630
|
CAAAGGGACACCAACAT2631
|
Haemophilia BTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTA2632
|
Cys73ArgATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAA
|
gTGT-CGTCTGTGAATTAGGTAAGTAACTATTTTTTGAATACT
|
AGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCT2633
|
TCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCAT
|
CCTTGCAACTGCCGCCATTTAAACATGGATTGGA
|
AATGTTGGTGTCCCTTT2634
|
AAAGGGACACCAACATT2635
|
Haemophilia BCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA2636
|
Cys73PheTTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAAC
|
TGT-TTTTGTGAATTAGGTAAGTAACTATTTTTTGAATACTC
|
GAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC2637
|
TTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCA
|
TCCTTGCAACTGCCGCCATTTAAACATGGATTGG
|
ATGTTGGTGTCCCTTTG2638
|
CAAAGGGACACCAACAT2639
|
Haemophilia BCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAAT2640
|
Cys73TermTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACT
|
TGTc-TGAGTGAATTAGGTAAGTAACTATTTTTTGAATACTCA
|
TGAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTC2641
|
CTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTC
|
ATCCTTGCAACTGCCGCCATTTAAACATGGATTG
|
TGTTGGTGTCCCTTTGG2642
|
CCAAAGGGACACCAACA2643
|
Haemophilia BGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGA2644
|
Gly76ValATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTA
|
GGA-GTAGGTAAGTAACTATTTTTTGAATACTCATGGTTCAA
|
TTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACA2645
|
GTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAA
|
TTAATGTCATCCTTGCAACTGCCGCCATTTAAAC
|
TCCCTTTGGATTTGAAG2646
|
CTTCAAATCCAAAGGGA2647
|
Haemophilia BTGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATG2648
|
Gly76ArgAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATT
|
tGGA-AGAAGGTAAGTAACTATTTTTTGAATACTCATGGTTCA
|
TGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACAG2649
|
TTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAAT
|
TAATGTCATCCTTGCAACTGCCGCCATTTAAACA
|
GTCCCTTTGGATTTGAA2650
|
TTCAAATCCAAAGGGAC2651
|
Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG2652
|
Phe77CysTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGT
|
TTT-TGTAAGTAACTATTTTTTGAATACTCATGGTTCAAAGT
|
ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC2653
|
ACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG
|
GAATTAATGTCATCCTTGCAACTGCCGCCATTTA
|
CTTTGGATTTGAAGGAA2654
|
TTCCTTCAAATCCAAAG2655
|
Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG2656
|
Phe77SerTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGT
|
TTT-TCTAAGTAACTATTTTTTGAATACTCATGGTTCAAAGT
|
ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC2657
|
ACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG
|
GAATTAATGTCATCCTTGCAACTGCCGCCATTTA
|
CTTTGGATTTGAAGGAA2658
|
TTCCTTCAAATCCAAAG2659
|
Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG2660
|
Phe77TyrTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGT
|
TTT-TATAAGTAACTATTTTTTGAATACTCATGGTTCAAAGT
|
ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC2661
|
ACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG
|
GAATTAATGTCATCCTTGCAACTGCCGCCATTTA
|
CTTTGGATTTGAAGGAA2662
|
TTCCTTCAAATCCAAAG2663
|
Haemophilia BAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTT2664
|
Glu78LysGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAA
|
tGAA-AAAGTAACTATTTTTTGAATACTCATGGTTCAAAGTTT
|
AAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAAT2665
|
TCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCAT
|
AGGAATTAATGTCATCCTTGCAACTGCCGCCATT
|
TTGGATTTGAAGGAAAG2666
|
CTTTCCTTCAAATCCAA2667
|
Haemophilia BGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT2668
|
Gly79ValGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAAGTA
|
GGA-GTAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCT
|
AGGGAAACTTTGAACCATGAGTATTCAAAAAAATAGTTACTTAC2669
|
CTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACA
|
TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC
|
ATTTGAAGGAAAGAACT2670
|
AGTTCTTTCCTTCAAAT2671
|
Haemophilia BGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGG2672
|
Gly79ArgTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAAGT
|
aGGA-AGAAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCC
|
GGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACC2673
|
TAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACAT
|
TCATAGGAATTAATGTCATCCTTGCAACTGCCGCC
|
GATTTGAAGGAAAGAAC2674
|
GTTCTTTCCTTCAAATC2675
|
Haemophilia BGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT2676
|
Gly79GluGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAAGTA
|
GGA-GAAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCT
|
AGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTAC2677
|
CTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACA
|
TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC
|
ATTTGAAGGAAAGAACT2678
|
AGTTCTTTCCTTCAAAT2679
|
Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT2680
|
Cys88SerCTTTTAGATGTAACATGTAACATTAAGAATGGCAGATGCGAGC
|
TGT-TCTAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT
|
ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC2681
|
TGCCATTCTTAATGTTACATGTTACATCTAAAAGAAGCAAAATA
|
GACAGTAACAGCATCATTTAACATGCATTTCTAA
|
TGTAACATGTAACATTA2682
|
TAATGTTACATGTTACA2683
|
Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT2684
|
Cys88PheCTTTTAGATGTAACATGTAACATTAAGAATGGCAGATGCGAGC
|
TGT-TTTAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT
|
ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC2685
|
TGCCATTCTTAATGTTACATGTTACATCTAAAAGAAGCAAAATA
|
GACAGTAACAGCATCATTTAACATGCATTTCTAA
|
TGTAACATGTAACATTA2686
|
TAATGTTACATGTTACA2687
|
Haemophilia BTTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCT2688
|
Cys88ArgTCTTTTAGATGTAACATGTAACATTAAGAATGGCAGATGCGAG
|
aTGT-CGTCAGTTTTGTAAAAATAGTGCTGATAACAAGGTGG
|
CCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATCT2689
|
GCCATTCTTAATGTTACATGTTACATCTAAAAGAAGCAAAATA
|
GACAGTAACAGCATCATTTAACATGCATTTCTAAA
|
ATGTAACATGTAACATT2690
|
AATGTTACATGTTACAT2691
|
Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT2692
|
Cys88TyrCTTTTAGATGTAACATGTAACATTAAGAATGGCAGATGCGAGC
|
TGT-TATAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT
|
ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC2693
|
TGCCATTCTTAATGTTACATGTTACATCTAAAAGAAGCAAAATA
|
GACAGTAACAGCATCATTTAACATGCATTTCTAA
|
TGTAACATGTAACATTA2694
|
TAATGTTACATGTTACA2695
|
Haemophilia BATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTA2696
|
Ile90ThrGATGTAACATGTAACATTAAGAATGGCAGATGCGAGCAGTTTT
|
ATT-ACTGTAAAAATAGTGCTGATAACAAGGTGGTTTGCTC
|
GAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAACTGCT2697
|
CGCATCTGCCATTCTTAATGTTACATGTTACATCTAAAAGAAG
|
CAAAATAGACAGTAACAGCATCATTTAACATGCAT
|
ATGTAACATTAAGAATG2698
|
CATTCTTAATGTTACAT2699
|
Haemophilia BTGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGT2700
|
Asn92HisAACATGTAACATTAAGAATGGCAGATGCGAGCAGTTTTGTAAA
|
gAAT-CATAATAGTGCTGATAACAAGGTGGTTTGCTCCTGTA
|
TACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAA2701
|
CTGCTCGCATCTGCCATTCTTAATGTTACATGTTACATCTAAAA
|
GAAGCAAAATAGACAGTAACAGCATCATTTAACA
|
ACATTAAGAATGGCAGA2702
|
TCTGCCATTCTTAATGT2703
|
Haemophilia BTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAA2704
|
Asn92LysCATGTAACATTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAA
|
AATg-AAATAGTGCTGATAACAAGGTGGTTTGCTCCTGTACT
|
AGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAA2705
|
AACTGCTCGCATCTGCCATTCTTAATGTTACATGTTACATCTA
|
AAAGAAGCAAAATAGACAGTAACAGCATCATTTAA
|
ATTAAGAATGGCAGATG2706
|
CATCTGCCATTCTTAAT2707
|
Haemophilia BAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACA2708
|
Gly93AspTGTAACATTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAATA
|
GGC-GACGTGCTGATAACAAGGTGGTTTGCTCCTGTACTGA
|
TCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTAC2709
|
AAAACTGCTCGCATCTGCCATTCTTAATGTTACATGTTACATCT
|
AAAAGAAGCAAAATAGACAGTAACAGCATCATTT
|
TAAGAATGGCAGATGCG2710
|
CGCATCTGCCATTCTTA2711
|
Haemophilia BTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAAC2712
|
Gly93SerATGTAACATTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAAT
|
tGGC-AGCAGTGCTGATAACAAGGTGGTTTGCTCCTGTACTG
|
CAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACA2713
|
AAACTGCTCGCATCTGCCATTCTTAATGTTACATGTTACATCTA
|
AAAGAAGCAAAATAGACAGTAACAGCATCATTTA
|
TTAAGAATGGCAGATGC2714
|
GCATCTGCCATTCTTAA2715
|
Haemophilia BGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTA2716
|
Arg94SerACATTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGC
|
AGAt-AGTTGATAACAAGGTGGTTTGCTCCTGTACTGAGGGA
|
TCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTT2717
|
TTACAAAACTGCTCGCATCTGCCATTCTTAATGTTACATGTTAC
|
ATCTAAAAGAAGCAAAATAGACAGTAACAGCATC
|
AATGGCAGATGCGAGCA2718
|
TGCTCGCATCTGCCATT2719
|
Haemophilia BTGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAAC2720
|
Cys95TyrATTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGCTG
|
TGC-TACATAACAAGGTGGTTTGCTCCTGTACTGAGGGATA
|
TATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTAT2721
|
TTTTACAAAACTGCTCGCATCTGCCATTCTTAATGTTACATGTT
|
ACATCTAAAAGAAGCAAAATAGACAGTAACAGCA
|
TGGCAGATGCGAGCAGT 2722
|
ACTGCTCGCATCTGCCA2723
|
Haemophilia BGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA2724
|
Cys95TrpTTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGCTGA
|
TGCg-TGGTAACAAGGTGGTTTGCTCCTGTACTGAGGGATAT
|
ATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA2725
|
TTTTTACAAAACTGCTCGCATCTGCCATTCTTAATGTTACATGT
|
TACATCTAAAAGAAGCAAAATAGACAGTAACAGC
|
GGCAGATGCGAGCAGTT2726
|
AACTGCTCGCATCTGCC2727
|
Haemophilia BGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA2728
|
Cys95TermTTAAGAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGCTGA
|
TGCg-TGATAACAAGGTGGTTTGCTCCTGTACTGAGGGATAT
|
ATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA2729
|
TTTTTACAAAACTGCTCGCATCTGCCATTCTTAATGTTACATGT
|
TACATCTAAAAGAAGCAAAATAGACAGTAACAGC
|
GGCAGATGCGAGCAGTT2730
|
AACTGCTCGCATCTGCC2731
|
Haemophilia BTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAG2732
|
Gln97ProAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGCTGATAACA
|
CAG-CCGAGGTGGTTTGCTCCTGTACTGAGGGATATCGACT
|
AGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCA2733
|
GCACTATTTTTACAAAACTGCTCGCATCTGCCATTCTTAATGTT
|
ACATGTTACATCTAAAAGAAGCAAAATAGACAGTA
|
ATGCGAGCAGTTTTGTA2734
|
TACAAAACTGCTCGCAT2735
|
Haemophilia BTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAA2736
|
Gln97GluGAATGGCAGATGCGAGCAGTTTTGTAAAAATAGTGCTGATAAC
|
gCAG-GAGAAGGTGGTTTGCTCCTGTACTGAGGGATATCGAC
|
GTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAG2737
|
CACTATTTTTACAAAACTGCTCGCATCTGCCATTCTTAATGTTA
|
CATGTTACATCTAAAAGAAGCAAAATAGACAGTAA
|
GATGCGAGCAGTTTTGT2738
|
ACAAAACTGCTCGCATC2739
|
Haemophilia BTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGG2740
|
Cys99ArgCAGATGCGAGCAGTTTTGTAAAAATAGTGCTGATAACAAGGTG
|
tTGT-CGTGTTTGCTCCTGTACTGAGGGATATCGACTTGCAG
|
CTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGT2741
|
TATCAGCACTATTTTTACAAAACTGCTCGCATCTGCCATTCTT
|
AATGTTACATGTTACATCTAAAAGAAGCAAAATAGA
|
AGCAGTTTTGTAAAAAT2742
|
ATTTTTACAAAACTGCT2743
|
Haemophilia BCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGGC2744
|
Cys99TyrAGATGCGAGCAGTTTTGTAAAAATAGTGCTGATAACAAGGTG
|
TGT-TATGTTTGCTCCTGTACTGAGGGATATCGACTTGCAGA
|
TCTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTG2745
|
TTATCAGCACTATTTTTACAAAACTGCTCGCATCTGCCATTCTT
|
AATGTTACATGTTACATCTAAAAGAAGCAAAATAG
|
GCAGTTTTGTAAAAATA2746
|
TATTTTTACAAAACTGC2747
|
Warfarin sensitivityTTTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTT2748
|
Ala(−10)ThrCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGA
|
cGCC-ACCGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC
|
GAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCG2749
|
ATTCAGAATTTTGTTGGCGTTTTCATGATCAAGAAAAACTGAAA
|
TGTAAAAGAATAATTCTTTAGTTTTAGCAAAAAA
|
ATGAAAACGCCAACAAA2750
|
TTTGTTGGCGTTTTCAT2751
|
Warfarin sensitivityTTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTTC2752
|
Ala(−10)ValTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAG
|
GCC-GTCGTATAATTCAGGTAAATTGGAAGAGTTTGTTCA
|
TGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCC2753
|
GATTCAGAATTTTGTTGGCGTTTTCATGATCAAGAAAAACTGA
|
AATGTAAAAGAATAATTCTTTAGTTTTAGCAAAAA
|
TGAAAACGCCAACAAAA2754
|
TTTTGTTGGCGTTTTCA2755
|
Haemophilia BTGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCCTCA2756
|
Gly(−26)ValTCACCATCTGCCTTTTAGGATATCTACTCAGTGCTGAATGTAC
|
GGA-GTAAGGTTTGTTTCCTTTTTTAAAATACATTGAGTATGC
|
GCATACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTC2757
|
AGCACTGAGTAGATATCCTAAAAGGCAGATGGTGATGAGGCC
|
TGGTGATTCTGCCATGATCATGTTCACGCGCTGCA
|
CCTTTTAGGATATCTAC2758
|
GTAGATATCCTAAAAGG2759
|
Haemophilia BTTATGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCC2760
|
Leu(−27)TermTCATCACCATCTGCCTTTTAGGATATCTACTCAGTGCTGAATG
|
TTA-TAATACAGGTTTGTTTCCTTTTTTAAAATACATTGAGTA
|
TACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTCAGC2761
|
ACTGAGTAGATATCCTAAAAGGCAGATGGTGATGAGGCCTGG
|
TGATTCTGCCATGATCATGTTCACGCGCTGCATAA
|
CTGCCTTTTAGGATATC2762
|
GATATCCTAAAAGGCAG2763
|
Haemophilia BTAGCAAAGGTTATGCAGCGCGTGAACATGATCATGGCAGAAT2764
|
Ile(−30)AsnCACCAGGCCTCATCACCATCTGCCTTTTAGGATATCTACTCAG
|
ATC-AACTGCTGAATGTACAGGTTTGTTTCCTTTTTTAAAATA
|
TATTTTAAAAAAGGAAACAAACCTGTACATTCAGCACTGAGTA2765
|
GATATCCTAAAAGGCAGATGGTGATGAGGCCTGGTGATTCTG
|
CCATGATCATGTTCACGCGCTGCATAACCTTTGCTA
|
CATCACCATCTGCCTTT2766
|
AAAGGCAGATGGTGATG2767
|
Haemophilia BACTAATCGACCTTACCACTTTCACAATCTGCTAGCAAAGGTTA2768
|
Ile(−40)PheTGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCCTCA
|
gATC-TTCTCACCATCTGCCTTTTAGGATATCTACTCAGTGCTG
|
CAGCACTGAGTAGATATCCTAAAAGGCAGATGGTGATGAGGC2769
|
CTGGTGATTCTGCCATGATCATGTTCACGCGCTGCATAACCTT
|
TGCTAGCAGATTGTGAAAGTGGTAAGGTCGATTAGT
|
TGAACATGATCATGGCA2770
|
TGCCATGATCATGTTCA2771
|
Haemophilia BACTTTGGTACAACTAATCGACCTTACCACTTTCACAATCTGCT2772
|
Arg(−44)HisAGCAAAGGTTATGCAGCGCGTGAACATGATCATGGCAGAATC
|
CGC-CACACCAGGCCTCATCACCATCTGCCTTTTAGGATATCT
|
AGATATCCTAAAAGGCAGATGGTGATGAGGCCTGGTGATTCT2773
|
GCCATGATCATGTTCACGCGCTGCATAACCTTTGCTAGCAGA
|
TTGTGAAAGTGGTAAGGTCGATTAGTTGTACCAAAGT
|
TATGCAGCGCGTGAACA2774
|
TGTTCACGCGCTGCATA2775
|
Alpha thalassemia—Hemoglobin alpha locus 1
[0140] The thalassemia syndromes are a heterogeneous group of inherited anemias characterized by defects in th synthesis of one or more globin chain subunits. For example, beta-thalassemia discussed in Example 6, is caused by a decrease in beta-chain production relative to alpha-chain production; the converse is the case for alpha-thalassemia. The attached table disclosed the correcting oligonucleotide base sequences for the hemoglobin alpha locus 1 oligonucleotides of the invention.
23TABLE 22
|
|
HBA1 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Thalassaemia alphaCCCTGGCGCGCTCGCGGCCCGGCACTCTTCTGGTCCCCACA2776
Met(-1)ValGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCCGACA
cATG-GTGAGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGC
GCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTTG2777
TCGGCAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGT
GGGGACCAGAAGAGTGCCGGGCCGCGAGCGCGCCAGGG
AACCCACCATGGTGCTG2778
CAGCACCATGGTGGGTT2779
Haemoglobin variantCACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC2780
Ala12AspGACAAGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGC
GCC-GACGCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTG
CACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC2781
GCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTTGTCGG
CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG
CGTCAAGGCCGCCTGGG2782
CCCAGGCGGCCTTGACG2783
Haemoglobin variantAGAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCA2784
Gly15AspACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCACGCTGG
GGT-GATCGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCT
AGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCGCC2785
AGCGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGG
TCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCTCT
CGCCTGGGGTAAGGTCG2786
CGACCTTACCCCAGGCG2787
Haemoglobin variantCTGCCGACAAGACCAACGTCAAGGCCGCCTGGGGTAAGGTC2788
Tyr24CysGGCGCGCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGA
TAT-TGTGGTGAGGCTCCCTCCCCTGCTCCGACCCGGGCTCCTCGCC
GGCGAGGAGCCCGGGTCGGAGCAGGGGAGGGAGCCTCACC2789
TCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGCGCCG
ACCTTACCCCAGGCGGCCTTGACGTTGGTCTTGTCGGCAG
TGGCGAGTATGGTGCGG2790
CCGCACCATACTCGCCA2791
Haemoglobin variantGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC2792
Glu27AspGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCT
GAGg-GATCCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC
C
GGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG2793
GGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCGCCAG
CGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTC
GGTGCGGAGGCCCTGGA2794
TCCAGGGCCTCCGCACC2795
Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG2796
Asn68LysTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGGACGA
AACg-AAGCATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG
CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG2797
TCGTCCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCAC
CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC
CTGACCAACGCCGTGGC2798
GCCACGGCGTTGGTCAG2799
Haemoglobin variantAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACC2800
Asp74GIyAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCTGTC
GAC-GGCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGGA
TCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGA2801
CAGCGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGG
TCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCT
GCACGTGGACGACATGC2802
GCATGTCGTCCACGTGC2803
Haemoglobin variantCAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGAC2804
Asp74HisCAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCTGT
gGAC-CACCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGG
CCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGAC2805
AGCGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGT
CAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTG
CGCACGTGGACGACATG2806
CATGTCGTCCACGTGCG2807
Haemoglobin variantCACGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGG2808
Asn78HisCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGAGC
cAAC-CACGACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACT
AGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCG2809
CTCAGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGC
CACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCGTG
ACATGCCCAACGCGCTG2810
CAGCGCGTTGGGCATGT2811
Haemoglobin variantACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCT2812
His87TyrGTCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGG
gCAC-TACACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGGAGCGA
TCGCTCCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCC2813
ACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGACAG
CGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGT
GCGACCTGCACGCGCAC2814
GTGCGCGTGCAGGTCGC2815
Haemoglobin variantGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA2816
Lys9OAsnGCGACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAAC
AAGc-AACTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAG
CTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT2817
TGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTC
AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC
GCGCACAAGCTTCGGGT2818
ACCCGAAGCTTGTGCGC2819
Haemoglobin variantTGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTG2820
Lys9OThrAGCGACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAA
AAG-ACGCTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGA
TCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGTT2821
GACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCA
GGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCCA
CGCGCACAAGCTTCGGG2822
CCCGAAGCTTGTGCGCG2823
Haemoglobin variantACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGAC2824
Arg92GlnCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACTTCAA
CGG-CAGGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCG
CGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTT2825
GAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGT
CGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTCCACGT
CAAGCTTCGGGTGGACC2826
GGTCCACCCGAAGCTTG2827
Haemoglobin variantACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCAC2828
Asp94GIyGCGCACAAGCTTCGGGTGGACCCGGTCAACTTCAAGGTGAG
GAC-GGCCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGG
CCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCT2829
CACCTTGAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGT
GCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGT
TCGGGTGGACCCGGTCA2830
TGACCGGGTCCACCCGA2831
Haemoglobin variantACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG2832
Pro95ArgCACAAGCTTCGGGTGGACCCGGTCAACTTCAAGGTGAGCGG
CCG-CGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGC
GCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC2833
GCTCACCTTGAAGTTGACCGGGTCCACCCGAAGCTTGTGCG
CGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGT
GGTGGACCCGGTCAACT2834
AGTTGACCGGGTCCACC2835
Haemoglobin variantCGGCGGCTGCGGGCCTGGGCCCTCGGCCCCACTGACCCTC2836
Ser102ArgTTCTCTGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCCTG
AGCc-AGAGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCAC
GTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCC2837
AGGGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCAGAGAA
GAGGGTCAGTGGGGCCGAGGGCCCAGGCCCGCAGCCGCCG
CTCCTAAGCCACTGCCT2838
AGGCAGTGGCTTAGGAG2839
Haemoglobin variantTTCTCTGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCCTG2840
Glu116LysGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGC
cGAG-AAGCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGC
GCACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCG2841
TGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCA
GGGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCAGAGAA
TCCCCGCCGAGTTCACC2842
GGTGAACTCGGCGGGGA2843
Haemogiobin variantTCCTAAGCCACIGCCTGCTGGTGACCCTGGCCGCCCACCTC2844
Ala120GluCCCGCCGAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAA
GCG-GAGGTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATA
TATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG2845
TCCAGGGAGGCGTGCACCGCAGGGGTGAACTCGGCGGGGA
GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA
CACCCCTGCGGTGCACG2846
CGTGCACCGCAGGGGTG2847
Thalassaemia alphaTGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCAC2848
Leu129ProGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCTG
CTG-CCGACCTCCAATACCGTTAAGCTGGAGCCTCGGTGGCCAT
ATGGCCACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGC2849
ACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG
CACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCA
CAAGTTCCTGGCTTCTG2850
CAGAAGCCAGGAACTTG2851
Haemoglobin variantTGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCG2852
Arg141LeuTGCTGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTGGCCA
CGT-CTTTGCTTCTTGCCCCTTGGGCCTCCCCCCAGCCCCTCCT
AGGAGGGGCTGGGGGGAGGCCCAAGGGGCAAGAAGCATGG2853
CCACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGCACG
GTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCA
CAAATACCGTTAAGCTG2854
CAGCTTAACGGTATTTG2855
Alpha-thalassemia—Hemoglobin alpha locus 2
[0141] The attached table discloses the correcting oligonucleotide base sequences for the hemoglobin alpha locus 2 oligonucleotides of the invention.
24TABLE 23
|
|
HBA2 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Thalassaemia alphaCCTGGCGCGCTCGCGGGCCGGCACTCTTCTGGTCCCCACAG2856
Met(-1)ThrACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAG
ATG-ACGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCA
TGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTT2857
GTCGGCAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCT
GTGGGGACCAGAAGAGTGCCGGCCCGCGAGCGCGCCAGG
ACCCACCATGGTGCTGT2858
ACAGCACCATGGTGGGT2859
Haemoglobin variantCACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC2860
Alal 2AspGACAAGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGC
GCC-GACGCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTG
CACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC2861
GCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTTGTCGG
CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG
CGTCAAGGCCGCCTGGG2862
CCCAGGCGGCCTTGACG2863
Haemoglobin variantAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCAAC2864
Lys16GluGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCACGCTGGCG
tAAG-GAGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCTCC
GGAGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCG2865
CCAGCGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTT
GGTCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCT
CCTGGGGTAAGGTCGGC2866
GCCGACCTTACCCCAGG2867
Haemoglobin variantGGTGCTGTCTCCTGCCGACAAGACCAACGTCAAGGCCGCCT2868
His20GlnGGGGTAAGGTCGGCGCGCACGCTGGCGAGTATGGTGCGGA
CACg-CAAGGCCCTGGAGAGGTGAGGCTCCCTCCCCTGCTCCGACCCG
CGGGTCGGAGCAGGGGAGGGAGCCTCACCTCTCCAGGGCC2869
TCCGCACCATACTCGCCAGCGTGCGCGCCGACCTTACCCCA
GGCGGCCTTGACGTTGGTCTTGTCGGCAGGAGACAGCACC
GGCGCGCACGCTGGCGA2870
TCGCCAGCGTGCGCGCC2871
Haemoglobin variantGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC2872
Glu27AspGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCT
GAGg-GACCCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC
C
GGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG2873
GGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCGCCAG
CGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTC
GGTGCGGAGGCCCTGGA2874
TCCAGGGCCTCCGCACC2875
Thalassaemia alphaACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCACGCTGG2876
Leu29ProCGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCTCC
CTG-CCGCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGACCCACAG
CTGTGGGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGG2877
GGAGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCG
CCAGCGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGT
GGAGGCCCTGGAGAGGT2878
ACCTCTCCAGGGCCTCC2879
Haemoglobin variantGCTTCTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAG2880
Asp47HisACCTACTTCCCGCACTTCGACCTGAGCCACGGCTCTGCCCA
cGAC-CACGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGA
TCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTGG2881
GCAGAGCCGTGGCTCAGGTCGAAGTGCGGGAAGTAGGTCTT
GGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAGAAGC
CGCACTTCGACCTGAGC2882
GCTCAGGTCGAAGTGCG2883
Haemoglobin variantCTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAGACCT2884
Leu48ArgACTTCCCGCACTTCGACCTGAGCCACGGCTCTGCCCAGGTTA
CTG-CGGAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACCAA
TTGGTCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAAC2885
CTGGGCAGAGCCGTGGCTCAGGTCGAAGTGCGGGAAGTAG
GTCTTGGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAG
CTTCGACCTGAGCCACG2886
CGTGGCTCAGGTCGAAG2887
Haemogiobin variantCTGTCCTTCCCCACCACCAAGACCTACTTCCCGCACTTCGAC2888
Gln54GluCTGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAA
cCAG-GAGGGTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGG
CCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCACCTTC2889
TTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTCAGGTC
GAAGTGCGGGAAGTAGGTCTTGGTGGTGGGGAAGGACAG
GCTCTGCCCAGGTTAAG2890
CTTAACCTGGGCAGAGC2891
Haemoglobin variantCCAAGACCTACTTCCCGCACTTCGACCTGAGCCACGGCTCTG2892
Gly59AspCCCAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCT
GGC-GACGACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGC
GCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAG2893
CGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTGGGCAG
AGCCGTGGCTCAGGTCGAAGTGCGGGAAGTAGGTCTTGG
GGGCCACGGCAAGAAGG2894
CCTTCTTGCCGTGGCCC2895
Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG2896
Asn68LysTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGGACGA
AACg-AACCATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG
CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG2897
TCGTCCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCAC
CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC
CTGACCAACGCCGTGGC2898
GCCACGGCGTTGGTCAG2899
Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG2900
Asn68LysTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGGACGA
AACg-AAACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG
CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG2901
TCGTCCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCAC_2901
CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC
CTGACCAACGCCGTGGC2902
GCCACGGCGTTGGTCAG2903
Haemoglobin variantCGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGGCG2904
Asn78LysCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGA
AACg-AAACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACTTC
GAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGT2905
CGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGC
GCCACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCG
ATGCCCAACGCGCTGTC2906
GACAGCGCGTTGGGCAT2907
Haemogiobin variantCGCTGACCAACGCCGTGGCGCACGTGGACGACATGCCCAAC2908
Asp85ValGCGCTGTCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCG
GAC-GTCGGTGGACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGG
CCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCCACCCG2909
AAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGACAGCGCGT
TGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAGCG
CCTGAGCGACCTGCACG2910
CGTGCAGGTCGCTCAGG2911
Haemoglobin variantGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA2912
Lys9OAsnGCGACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAAC
AAGc-AATTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAG
CTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT2913
TGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTC
AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC
GCGCACAAGCTTCGGGT2914
ACCCGAAGCTTGTGCGC2915
Haemoglobin variantGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCA2916
Asp94HisCGCGCACAAGCTTCGGGTGGACCCGGTCAACTTCAAGGTGA
gGAC-CACGCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATG
CATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTC2917
ACCTTGAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTG
CAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTC
TTCGGGTGGACCCGGTC2918
GACCGGGTCCACCCGAA2919
Haemoglobin variantACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG2920
Pro95LeuCACAAGCTTCGGGTGGACCCGGTCAACTTCAAGGTGAGCGG
CCG-CTGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGC
GCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC2921
GCTCACCTTGAAGTTGACCGGGTCCACCCGAAGCTTGTGCG
CGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGT
GGTGGACCCGGTCAACT2922
AGTTGACCGGGTCCACC2923
Haemoglobin variantTAGCGCAGGCGGCGGCTGCGGGCCTGGGCCGCACTGACCC2924
Ser102ArgTCTTCTCTGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCC
aAGC-CGCTGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGC
GCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCAG2925
GGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCAGAGAAGA
GGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCCTGCGCTA
AGCTCCTAAGCCACTGC2926
GCAGTGGCTTAGGAGCT2927
Haemoglobin H diseaseGGCGGCGGCTGCGGGCCTGGGCCGCACTGACCCTCTTCTCT2928
Cys104TyrGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGC
TGC-TACCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTC
GAGGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGG2929
CGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCA
GAGAAGAGGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCC
AAGCCACTGCCTGCTGG2930
CCAGCAGGCAGTGGCTT2931
Haemoglobin variantCCGCACTGACCCTCTTCTCTGCACAGCTCCTAAGCCACTGCC2932
Ala111ValTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGAGTTCACC
GCC-GTCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTGGCTTC
GAAGCCAGGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGT2933
GAACTCGGCGGGGAGGTGGGCGGCCAGGGTCACCAGCAGG
CAGTGGCTTAGGAGCTGTGCAGAGAAGAGGGTCAGTGCGG
CCTGGCCGCCCACCTCC2934
GGAGGTGGGCGGCCAGG2935
Haemoglobin variantTCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTC2936
Ala120GluCCCGCCGAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAA
GCG-GAGGTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATA
TATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG2937
TCCAGGGAGGCGTGCACCGCAGGGGTGAACTCGGCGGGGA
GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA
CACCCCTGCGGTGCACG2938
CGTGCACCGCAGGGGTG2939
Haemoglobin variantCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCG2940
His122GlnAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTG
CACg-CAGGCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAA
TTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAG2941
GAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACTCGG
CGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTGG
GCGGTGCACGCCTCCCT2942
AGGGAGGCGTGCACCGC2943
Haemoglobin variantCACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGA2944
Ala123SerGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTGG
cGCC-TCCCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAG
CTTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCA2945
GGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACTCG
GCGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTG
CGGTGCACGCCTCCCTG2946
CAGGGAGGCGTGCACCG2947
Thalassaemia alphaTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGAGTTCACC2948
Leu125ProCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGT
CTG-CCGGAGCACCGTGCTGACCTCCAAATACCGTTAAGCTGGAGC
GCTCCAGCTTAACGGTATTTGGAGGTCAGCACGGTGCTCACA2949
GAAGCCAGGAACTTGTCCAGGGAGGCGTGCACCGCAGGGG
TGAACTCGGCGGGGAGGTGGGCGGCCAGGGTCACCAGCA
CGCCTCCCTGGACAAGT2950
ACTTGTCCAGGGAGGCG2951
Haemoglobin variantGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTC2952
Ser131ProCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCTGACCTC
tTCT-CCTCAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTTCCTC
GAGGAACGGCTACCGAGGCTCCAGCTTAACGGTATTTGGAG2953
GTCAGCACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGA
GGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGC
TCCTGGCTTCTGTGAGC2954
GCTCACAGAAGCCAGGA2955
Haemoglobin variantGAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCT2956
Leu136MetGGCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAGC
gCTG-ATGTGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCT
AGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAGC2957
TTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAG
GAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACTC
GCACCGTGCTGACCTCC2958
GGAGGTCAGCACGGTGC2959
Haemoglobin variantAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTG2960
Leu136ProGCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAGCT
CTG-CCGGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTC
GAGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAG2961
CTTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCA
GGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACT
CACCGTGCTGACCTCCA2962
TGGAGGTCAGCACGGTG2963
Haemoglobin variantGTGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACC2964
Arg141CysGTGCTGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTAGCC
cCGT-TGTGTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCC
GGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAACGGC2965
TACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGCACGGT
GCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCAC
CCAAATACCGTTAAGCT2966
AGCTTAACGGTATTTGG2967
Haemoglobin variantCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG2968
Term142GlnCTGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTT
tTAA-CAACCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCC
GGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC2969
GGCTACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGCA
CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG
AATACCGTTAAGCTGGA2970
TCCAGCTTAACGGTATT2971
Haemoglobin variantCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG2972
Term142LysCTGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTT
tTAA-AAACCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCC
GGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC2973
GGCTACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGCA
CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG
AATACCGTTAAGCTGGA2974
TCCAGCTTAACGGTATT2975
Haemoglobin variantCGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCT2976
Term142TyrGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTTCC
TAAg-TATTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCC
GGGGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGG2977
AACGGCTACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAG
CACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCG
TACCGTTAAGCTGGAGC2978
GCTCCAGCTTAACGGTA2979
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Human Mismatch Repair—MLH1
[0142] The human MLH1 gene is homologous to the bacterial mutL gene, which is involved in mismatch repair. Mutations in the MLH1 gene have been identified in many individuals with hereditary nonpolyposis colorectal cancer (HNPCC). Mutations in the MLH1 gene are also implicated in predisposition to a variety of cancers associated with, for example, Muir-Torre syndrome and Turcot syndrome. The attached table discloses the correcting oligonucleotide base sequences for the MLH1 oligonucleotides of the invention.
25TABLE 24
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MLH1 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO
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Non-polyposisTTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG2980
colorectal cancerGCTCTTCTGGCGCCAAAATGTCGTTCGTGGCAGGGGTTATTC
Met1ArgGGCGGCTGGACGAGACAGTGGTGAACCGCATCGCGGC
ATG-AGGGCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT2981
AACCCCTGCCACGAACGACATTTTGGCGCCAGAAGAGCCAA
GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA
CGCCAAAATGTCGTTCG2982
CGAACGACATTTTGGCG2983
Non-polyposisTTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG2984
colorectal cancerGCTCTTCTGGCGCCAAAATGTCGTTCGTGGCAGGGGTTATTC
Met1LysGGCGGCTGGACGAGACAGTGGTGAACCGCATCGCGGC
ATG-AAGGCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT2985
AACCCCTGCCACGAACGACATTTTGGCGCCAGAAGAGCCAA
GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA
CGCCAAAATGTCGTTCG2986
CGAACGACATTTTGGCG2987
Non-polyposisTGGTGAACCGCATCGCGGCGGGGGAAGTTATCCAGCGGCCA2988
colorectal cancerGCTAATGCTATCAAAGAGATGATTGAGAACTGGTACGGAGGG
Met35ArgAGTCGAGCCGGGCTCACTTAAGGGCTACGACTTAACGG
ATG-AGGCCGTTAAGTCGTAGCCCTTAAGTGAGCCCGGCTCGACTCCCT2989
CCGTACCAGTTCTCAATCATCTCTTTGATAGCATTAGCTGGCC
GCTGGATAACTTCCCCCGCCGCGATGCGGTTCACCA
CAAAGAGATGATTGAGA2990
TCTCAATCATCTCTTTG2991
Non-polyposisTAGAGTAGTTGCAGACTGATAAATTATTTTCTGTTTGATTTGCC2992
colorectal cancerAGTTTAGATGCAAAATCCACAAGTATTCAAGTGATGTTAAAG
Ser44PheAGGGAGGCCTGAAGTTGATTCAGATCCAAGACAA
TCC-TTCTTGTCTTGGATCTGAATCAACTTCAGGCCTCCCTCTTTAACAA2993
TCACTTGAATACTTGTGGATTTTGCATCTAAACTGGCAAATCA
AACAGAAAATAATTTATCAGTCTGCAACTACTCTA
TGCAAAATCCACAAGTA2994
TACTTGTGGATTTTGCA2995
Non-polyposisGCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC2996
colorectal cancerCTGAAGTTGATTCAGATCCAAGACAATGGCACCGGGATCAGG
Gln62LysGTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC
CAA-AAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT2997
CCCGGTGCCATTGTCTTGGATCTGAATCAACTTCAGGCCTCC
CTCTTTTAACAATCACTTGAATACTTGTGGATTTTGC
TTCAGATCCAAGACAAT2998
ATTGTCTTGGATCTGAA2999
Non-polyposisGCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC3000
colorectal cancerCTGAAGTTGATTCAGATCCAAGACAATGGCACCGGGATCAGG
Gln62TermGTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC
CAA-TAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT3001
CCCGGTGCCATTGTCTTGGATCTGAATCAACTTCAGGCCTCC
CTCTTTAACAATCACTTGAATACTTGTGGATTTTGC
TTCAGATCCAAGACAAT3002
ATTGTCTTGGATCTGAA3003
Non-polyposisCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGT3004
colorectal cancerTGATTCAGATCCAAGACAATGGCACCGGGATCAGGGTAAGTA
Asn64SerAAACCTCAAAGTAGCAGGATGTTTGTGCGCTTCATGG
AAT-AGTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTA3005
CCCTGATCCCGGTGCCATTGTCTTGGATCTGAATCAACTTCA
GGCCTCCCTCTTTAACAATCACTTGAATACTTGTGG
CCAAGACAATGGCACCG3006
CGGTGCCATTGTCTTGG3007
Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA3008
colorectal cancerTCCAAGACAATGGCACCGGGATCAGGGTAAGTAAAACCTCAA
Gly67ArgAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA
GGG-AGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT3009
TTTACTTACCCTGATCCCGGTGCCATTGTCTTGGATCTGAATC
AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT
ATGGCACCGGGATCAGG3010
CCTGATCCCGGTGCCAT3011
Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA3012
colorectal cancerTCCAAGACAATGGCACCGGGATCAGGGTAAGTAAAACCTCAA
Gly67ArgAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA
GGG-CGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT3013
TTTACTTACCCTGATCCCGGTGCCATTGTCTTGGATCTGAATC
AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT
ATGGCACCGGGATCAGG3014
CCTGATCCCGGTGCCAT3015
Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA3016
colorectal cancerTCCAAGACAATGGCACCGGGATCAGGGTAAGTAAAACCTCAA
Gly67TrpAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA
GGG-TGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT3017
TTTACTTACCCTGATCCCGGTGCCATTGTCTTGGATCTGAATC
AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT
ATGGCACCGGGATCAGG3018
CCTGATCCCGGTGCCAT3019
Non-polyposisGTAACATGATTATTTACTCATCTTTTTGGTATCTAACAGAAAGA3020
colorectal cancerAGATCTGGATATTGTATGTGAAAGGTTCACTACTAGTAAACTG
Cys77ArgCAGTCCTTTGAGGATTTAGCCAGTATTTCTACCT
TGT-CGTAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTACT3021
AGTAGTGAACCTTTCACATACAATATCCAGATCTTCTTCTGTT
AGATACCAAAAAGATGAGTAAATAATCATGTTAC
ATATTGTATGTGAAAGG3022
CCTTTCACATACAATAT3023
Non-polyposisTAACATGATTATTTACTCATCTTTTTGGTATCTAACAGAAAGAA3024
colorectal cancerGATCTGGATATTGTATGTGAAAGGTTCACTACTAGTAAACTGC
Cys77TyrAGTCCTTTGAGGATTTAGCCAGTATTTCTACCTA
TGT-TATTAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTAC3025
TAGTAGTGAACCTTTCACATACAATATCCAGATCTTCTTTCTGT
TAGATACCAAAAAGATGAGTAAATAATCATGTTA
TATTGTATGTGAAAGGT3026
ACCTTTCACATACAATA3027
Non-polyposisCTGGATATTGTATGTGAAAGGTTCACTACTAGTAAACTGCAGT3028
colorectal cancerCCTTTGAGGATTTAGCCAGTATTTCTACCTATGGCTTTCGAGG
Ser93GlyTGAGGTAAGCTAAAGATTTCAAGAAATGTGTAAAAT
AGT-GGTATTTTACACATTTCTTGAATCTTTAGCTTACCTCACCTCGAAAG3029
CCATAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTT
TACTAGTAGTGAACCTTTCACATACAATATCCAG
ATTTAGCCAGTATTTCT3030
AGAAATACTGGCTAAAT3031
Non-polyposisTTCACTACTAGTAAACTGCAGTCCTTTGAGGATTTAGCCAGTA3032
colorectal cancerTTTCTACCTATGGCTTTCGAGGTGAGGTAAGCTAAAGATTCAA
Arg100TermGAAATGTGTAAAATATCCTCCTGTGATGACATTGT
CGA-TGAACAATGTCATCACAGGAGGATATTTTACACATTTCTTGAATCTT3033
TAGCTTACCTCACCTCGAAAGCCATAGGTAGAAATACTGGCTA
AATCCTCAAAGGACTGCAGTTTACTAGTAGTGAA
ATGGCTTTCGAGGTGAG3034
CTCACCTCGAAAGCCAT3035
Non-polyposisACCCAGCAGTGAGTTTTTCTTTCAGTCTATTTTCTTTCTTCCT3036
colorectal cancerTAGGCTTGGCCAGCATAAGCCATGTGGCTCATGTTACTATTA
Ile107ArgCAACGAAAACAGCTGATGGAAAGTGTGCATACAG
ATA-AGACTGTATGCACACTTTCCATCAGCTGTTTTCGTTGTAATAGTAA3037
CATGAGCCACATGGCTTATGCTGGCCAAAGCCTAAGGAAGAA
AAGAAAATAGACTGAAAGAAAAACTCACTGCTGGGT
GGCCAGCATAAGCCATG3038
CATGGCTTATGCTGGCC3039
Non-polyposisTTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC3040
colorectal cancerTCATGTTACTATTACAACGAAAACAGCTGATGGAAAGTGTGCA
Thr117ArgTACAGGTATAGTGCTGACTTCTTTTACTCATATAT
ACG-AGGATATATGAGTAAAAGAAGTCAGCACTATACCTGTATGCACACT3041
TTCCATCAGCTGTTTTCGTTGTAATAGTAACATGAGCCACATG
GCTTATGCTGGCCAAAGCCTAAGGAAGAAAAGAAA
TATTACAACGAAAACAG3042
CTGTTTTCGTTGTAATA3043
Non-polyposisTTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC3044
colorectal cancerTCATGTTACTATTACAACGAAAACAGCTGATGGAAAGTGTGCA
Thr117MetTACAGGTATAGTGCTGACTTCTTTTACTCATATAT
ACG-ATGATATATGAGTAAAAGAAGTCAGCACTATACCTGTATGCACACT3045
TTCCATCAGCTGTTTTCGTTGTAATAGTAACATGAGCCACATG
GCTTATGCTGGCCAAAGCCTAAGGAAGAAAAGAAA
TATTACAACGAAAACAG3046
CTGTTTTCGTTGTAATA3047
Non-polyposisTCTATCTCTCTACTGGATATTAATTTGTTATATTTTCTCATTAGA3048
colorectal cancerGCAAGTTACTCAGATGGAAAACTGAAAGCCCCTCCTAAACCA
Gly133TermTGTGCTGGCAATCAAGGGACCCAGATCACGGTAA
GGA-TGATTACCGTGATCTGGGTCCCTTGATTGCCAGCACATGGTTTAG3049
GAGGGGCTTTCAGTTTTCCATCTGAGTAACTTGCTCTAATGAG
AAAATATAACAAATTAATATCCAGTAGAGAGATAGA
ACTCAGATGGAAAACTG3050
CAGTTTTCCATCTGAGT3051
Non-polyposisTAGTGTGTGTTTTTGGCAACTCTTTTCTTACTCTTTTGTTTTTC3052
colorectal cancerTTTTCCAGGTATTCAGTACACAATGCAGGCATTAGTTTCTCAG
Val185GlyTTAAAAAAGTAAGTTCTTGGTTTATGGGGGATGG
GTA-GGACCATCCCCCATAAACCAAGAACTTACTTTTTTAACTGAGAAAC3053
TAATGCCTGCATTGTGTACTGAATACCTGGAAAAGAAAACAA
AAGAGTAAGAAAAGAGTTGCCAAAAACACACACTA
GTATTCAGTACACAATG3054
CATTGTGTACTGAATAC3055
Non-polyposisTTTCTTACTCTTTTGTTTTTCTTTTCCAGGTATTCAGTACACAAT3056
colorectal cancerGCAGGCATTAGTTTCTCAGTTAAAAAAGTAAGTTCTTGGTTTAT
Ser193ProGGGGGATGGTTTTTGTTTTATGAAAAGAAAAAA
TCA-CCATTTTTTCTTTTCATAAAACAAAACCATCCCCCATAAACCAAGAA3057
CTTACTTTTTTAACTGAGAAACTAATGCCTGCATTGTGTACTG
AATACCTGGAAAAGAAAAACAAAAGAGTAAGAAA
TTAGTTTTCTCAGTTAAA3058
TTTAACTGAGAAACTAA3059
Non-polyposisTTTGTTTATCAGCAAGGAGAGACAGTAGCTGATGTTAGGACA3060
colorectal cancerCTACCCAATGCCTCAACCGTGGACAATATTCGCTCCATCTTTG
Val213MetGAAATGCTGTTAGTCGGTATGTCGATAACCTATATA
GTG-ATGTATATAGGTTATCGACATACCGACTAACAGCATTTCCAAAGAT3061
GGAGCGAATATTGTCCACGGTTGAGGCATTGGGTAGTGTCCT
AACATCAGCTACTGTCTCTCCTTGCTGATAAACAAA
CCTCAACCGTGGACAAT3062
ATTGTCCACGGTTGAGG3063
Non-polyposisCAAGGAGAGACAGTAGCTGATGTTAGGACACTACCCAATGCC3064
colorectal cancerTCAACCGTGGACAATATTCGCTCCATCTTTGGAAATGCTGTTA
Arg217CysGTCGGTATGTCGATAACCTATATAAAAAAATCTTTT
CGC-TGCAAAAGATTTTTTTATATAGGTTATCGACATACCGACTAACAGCA3065
TTTCCAAAGATGGAGCGAATATTGTCCACGGTTGAGGCATTG
GGTAGTGTCCTAACATCAGCTACTGTCTCTCCTTG
ACAATATTCGCTCCATC3066
GATGGAGCGAATATTGT3067
Non-polyposisGAGACAGTAGCTGATGTTAGGACACTACCCAATGCCTCAACC3068
colorectal cancerGTGGACAATATTCGCTCCATCTTTGGAAATGCTGTTAGTCGGT
Ile219ValATGTCGATAACCTATATAAAAAAATCTTTTACATTT
ATC-GTCAAATGTAAAAGATTTTTTTATATAGGTTATCGACATACCGACTA3069
ACAGCATTTCCAAAGATGGAGCGAATATTGTCCACGGTTTGAG
GCATTGGGTAGTGTCCTAACATCAGCTACTGTCTC
TTCGCTCCATCTTTGGA3070
TCCAAAGATGGAGCGAA3071
Non-polyposisCTAATAGAGAACTGATAGAAATTGGATGTGAGGATAAAACCCT3072
colorectal cancerAGCCTTCAAAATGAATGGTTACATATCCAATGCAAACTACTCA
Gly244AspGTGAAGAAGTGCATCTTCTTACTCTTCATCAACCG
GGT-GATCGGTTGATGAAGAGTAAGAAGATGCACTTCTTCACTGAGTAG3073
TTTGCATTGGATATGTAACCATTTCATTTTGAAGGCTAGGGTTT
TATCCTCACATCCAATTTCTATCAGTTCTCTATTAG
AATGAATGGTTACATAT3074
ATATGTAACCATTCATT3075
Non-polyposisGATGTGAGGATAAAACCCTAGCCTTCAAAATGAATGGTTACAT3076
colorectal cancerATCCAATGCAAACTACTCAGTGAAGAAGTGCATCTTCTTACTC
Ser252TermTTCATCAACCGTAAGTTAAAAAGAACCACATGGGA
TCA-TAATCCCATGTGGTTCTTTTTTAACTTACGGTTGATGAAGAGTAAGA3077
AGATGCACTTCTTCACTGAGTAGTTTGCATTGGATATGTAACC
ATTCATTTTGAAGGCTAGGGTTTTATCCTCACATC
AAACTACTCAGTGAAGA3078
TCTTCACTGAGTAGTTT3079
Non-polyposisCACCCCTCAGGACAGTTTTTGAACTGGTTGCTTTCTTTTTATTG3080
colorectal cancerTTTAGATCGTCTGGTAGAATCAACTTCCTTGAGAAAAGCCATA
Glu268GlyGAAACAGTGTATGCAGCCTATTTGCCCAAAAACAC
GAA-GGAGTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGGCTT3081
TCTCAAGGAAGTTGATTCTACCAGACGATCTAAACAATAAAA
AGAAAGCAACCAGTTCAAAACTGTCCTGAGGGGTG
TCTGGTAGAATCAACTT3082
AAGTTGATTCTACCAGA3083
Non-polyposisCCCTCAGGACAGTTTTGAACTGGTTGCTTTCTTTTTATTGTTTA3084
colorectal cancerGATCGTCTGGTAGAATCAACTTCCTTGAGAAAAGCCATAGAAA
Ser269TermCAGTGTATGCAGCCTATTTGCCCAAAAACACACA
TCA-TGATGTGTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGG3085
CTTTTCTCAAGGAAGTTGATTCTACCAGACGATCTAAACAATA
AAAAGAAAGCAACCAGTTCAAAACTGTCCTGAGGG
GGTAGAATCAACTTCCT3086
AGGAAGTTGATTCTACC3087
Non-polyposisCTTTTTCTCCCCCTCCCACTATCTAAGGTAATTGTTCTCTCTTA3088
colorectal cancerTTTTCCTGACAGTTTAGAAATCAGTCCCCAGAATGTGGATGTT
Glu297TermAATGTGCACCCCACAAAGCATGAAGTTCACTTCC
GAA-TAAGGAAGTGAACTTCATGCTTTGTGGGGTGCACATTAACATCCA3089
CATTCTGGGGACTGATTTCTAAACTGTCAGGAAAATAAGAGAG
AACAATTACCTTAGATAGTGGGAGGGGGAGAAAAAG
ACAGTTTAGAAATCAGT3090
ACTGATTTCTAAACTGT3091
Non-polyposisCTCCCACTATCTAAGGTAATTGTTCTCTCTTATTTTCCTGACAG3092
colorectal cancerTTTAGAAATCAGTCCCCAGAATGTGGATGTTAATGTGCACCCC
Gln301TermACAAAGCATGAAGTTCACTTCCTGCACGAGGAGA
CAG-TAGTCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCA3093
CATTAACATCCACATTCTGGGGACTGATTTCTAAACTGTCAGG
AAAATAAGAGAGAACAATTACCTTAGATAGTGGGAG
TCAGTCCCCAGAATGTG3094
CACATTCTGGGGACTGA3095
Non-polyposisATGTGCACCCCACAAAGCATGAAGTTCACTTCCTGCACGAGG3096
colorectal cancerAGAGCATCCTGGAGCGGGTGCAGCAGCACATCGAGAGCAAG
Val326AlaCTCCTGGGCTCCAATTCCTCCAGGATGTACTTCACCCA
GTG-GCGTGGGTGAAGTACATCCTGGAGGAATTGGAGCCCAGGAGCTT3097
GCTCTCGATGTGCTGCTGCACCCGCTCCAGGATGCTCTCCT
CGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCACAT
GGAGCGGGTGCAGCAGC3098
GCTGCTGCACCCGCTCC3099
Non-polyposisCCACAAAGCATGAAGTTCACTTCCTGCACGAGGAGAGCATCC3100
colorectal cancerTGGAGCGGGTGCAGCAGCACATCGAGAGCAAGCTCCTGGGC
His329ProTCCAATTCCTCCAGGATGTACTTCACCCAGGTCAGGGC
CAC-CCCGCCCTGACCTGGGTGAAGTACATCCTGGAGGAATTGGAGCC3101
CAGGAGCTTGCTCTCGATGTGCTGCTGCACCCGCTCCAGGA
TGCTCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGG
GCAGCAGCACATCGAGA3102
TCTCGATGTGCTGCTGC3103
Non-polyposisCAAGTCTGACCTCGTCTTCTACTTCTGGAAGTAGTGATAAGGT3104
colorectal cancerCTATGCCCACCAGATGGTTCGTACAGATTCCCGGGAACAGAA
Val384AspGCTTGATGCATTTCTGCAGCCTCTGAGCAAACCCCT
GTT-GATAGGGGTTTGCTCAGAGGCTGCAGAAATGCATCAAGCTTCTGT3105
TCCCGGGAATCTGTACGAACCATCTGGTGGGCATAGACCTTA
TCACTACTTCCAGAAGTAGAAGACGAGGTCAGACTTG
CCAGATGGTTCGTACAG3106
CTGTACGAACCATCTGG3107
Non-polyposisAGTGGCAGGGCTAGGCAGCAAGATGAGGAGATGCTTGAACT3108
colorectal cancerCCCAGCCCCTGCTGAAGTGGCTGCCAAAAATCAGAGCTTGGA
Ala441ThrGGGGGATACAACAAAGGGGACTTCAGAAATGTCAGAGA
GCT-ACTTCTCTGACATTTCTGAAGTCCCCTTTGTTGTATCCCCCTCCAA3109
GCTCTGATTTTTGGCAGCCACTTCAGCAGGGGCTGGGAGTTC
AAGCATCTCCTCATCTTGCTGCCTAGCCCTGCCACT
CTGAAGTGGCTGCCAAA3110
TTTGGCAGCCACTTCAG3111
Non-polyposisCTTCATTGCAGAAAGAGACATCGGGAAGATTCTGATGTGGAA3112
colorectal cancerATGGTGGAAGATGATTCCCGAAAGGAAATGACTGCAGCTTGT
Arg487TermACCCCCCGGAGAAGGATCATTAACCTCACTAGTGTTT
CGA-TGAAAACACTAGTGAGGTTAATGATCCTTCTCCGGGGGGTACAAG3113
CTGCAGTCATTTCCTTTCGGGAATCATCTTCCACCATTTCCAC
ATCAGAATCTTCCCGATGTCTCTTTCTGCAATGAAG
ATGATTCCCGAAAGGAA3114
TTCCTTTCGGGAATCAT3115
Non-polyposisAGACATCGGGAAGATTCTGATGTGGAAATGGTGGAAGATGAT3116
colorectal cancerTCCCGAAAGGAAATGACTGCAGCTTGTACCCCCCGGAGAAG
Ala492ThrGATCATTAACCTCACTAGTGTTTTGAGTCTCCAGGAAG
GCA-ACACTTCCTGGAGACTCAAAACACTAGTGAGGTTAATGATCCTTCT3117
CCGGGGGGTACAAGCTGCAGTCATTTCCTTTCGGGAATCATC
TTCCACCATTTCCACATCAGAATCTTCCCGATGTCT
AAATGACTGCAGCTTGT3118
ACAAGCTGCAGTCATTT3119
Non-polyposisCCCGAAAGGAAATGACTGCAGCTTGTACCCCCCGGAGAAGG3120
colorectal cancerATCATTAACCTCACTAGTGTTTTGAGTCTCCAGGAAGAAATTA
Val506AlaATGAGCAGGGACATGAGGGTACGTAAACGCTGTGGCC
GTT-GCTGGCCACAGCGTTTACGTACCCTCATGTCCCTGCTCATTAATTT3121
CTTCCTGGAGACTCAAAACACTAGTGAGGTTAATGATCCTTCT
CCGGGGGGTACAAGCTGCAGTCATTTCCTTTCGGG
CACTAGTGTTTTGAGTC3122
GACTCAAAACACTAGTG3123
Non-polyposisGGGAGATGTTGCATAACCACTCCTTCGTGGGCTGTGTGAATC3124
colorectal cancerCTCAGTGGGCCTTGGCACAGCATCAAACCAAGTTATACCTTC
Gln542LeuTCAACACCACCAAGCTTAGGTAAATCAGCTGAGTGTG
CAG-CTGCACACTCAGCTGATTTACCTAAGCTTGGTGGTGTTGAGAAGG3125
TATAACTTGGTTTGATGCTGTGCCAAGGCCCACTGAGGATTC
ACACAGCCCACGAAGGAGTGGTTATGCAACATCTCCC
CTTGGCACAGCATCAAA3126
TTTGATGCTGTGCCAAG3127
Non-polyposisCCTTCGTGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAG3128
colorectal cancerCATCAAACCAAGTTATACCTTCTCAACACCACCAAGCTTAGGT
Leu549ProAAATCAGCTGAGTGTGTGAACAAGCAGAGCTACTACA
CTT-CCTTGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATTTACCTAA3129
GCTTGGTGGTGTTGAGAAGGTATAACTTGGTTTGATGCTGTG
CCAAGGCCCACTGAGGATTCACACAGCCCACGAAGG
GTTATACCTTCTCAACA3130
TGTTGAGAAGGTATAAC3131
Non-polyposisTGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAGCATCAAA3132
colorectal cancerCCAAGTTATACCTTCTCAACACCACCAAGCTTAGGTAAATCAG
Asn55lThrCTGAGTGTGTGAACAAGCAGAGCTACTACAACAATG
AAC-ACCCATTGTTGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATT3133
ACCTAAGCTTTGGTGGTGTTGAGAAGGTATAACTTGGTTTGATG
CTGTGCCAAGGCCCACTGAGGATTCACACAGCCCA
CCTTCTCAACACCACCA3134
TGGTGGTGTTGAGAAGG3135
Non-polyposisATGAATTCAGCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAG3136
colorectal cancerTGAAGAACTGTTCTACCAGATACTCATTTATGATTTTGCCAACTT
Gln562TermTTGGTGTTCTCAGGTTATCGGTAAGTTTAGATC
CAG-TAGGATCTAAACTTACCGATAACCTGAGAACACCAAAATTGGCAAA3137
ATCATAAATGAGTATCTGGTAGAACAGTTCTTCACTGAAAATA
AAAATGAAGTGACTTTAAGGAAAAGCTGAATTCAT
TGTTCTACCAGATACTC3138
GAGTATCTGGTAGAACA3139
Non-polyposisGCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAGTGAAGAACT3140
colorectal cancerGTTCTACCAGATACTCATTTATGATTTTGCCAATTTTGGTGTTC
Ile565PheTCAGGTTATCGGTAAGTTTAGATCCTTTTCACT
ATT-TTTAGTGAAAAGGATCTAAACTTACCGATAACCTGAGAACACCAAA3141
ATTGGCAAAATCATAAATGAGTATCTGGTAGAACAGTTCTTCA
CTGAAAATAAAAATGAAGTGACTTTAAGGAAAAGC
AGATACTCATTTATGAT3142
ATCATAAATGAGTATCT3143
Non-polyposisTTTTCAGTGAAGAACTGTTCTACCAGATACTCATTTATGATTTT3144
colorectal cancerGCCAATTTTGGTGTTCTCAGGTTATCGGTAAGTTTAGATCCTT
Leu574ProTTCACTTCTGAAATTTCAACTGATCGTTTCTGAA
CTC-CCCTTCAGAAACGATCAGTTGAAATTTCAGAAGTGAAAAGGATCTA3145
AACTTACCGATAACCTGAGAACACCAAAATTGGCAAAATCATA
AATGAGTATCTGGTAGAACAGTTCTTCACTGAAAA
TGGTGTTCTCAGGTTTAT3146
ATAACCTGAGAACACCA3147
Non-potyposisTGGATGCTCCGTTAAAGCTTGCTCCTTCATGTTCTTGCTTCTT3148
colorectal cancerCCTAGGAGCCAGCACCGCTCTTTGACCTTGCCATGCTTGCCT
Leu582ValTAGATAGTCCAGAGAGTGGCTGGACAGAGGAAGATG
CTC-GTCCATCTTCCTCTGTCCAGCCACTCTCTGGACTATCTAAGGCAA3149
GCATGGCAAGGTCAAAGAGCGGTGCTGGCTCCTAGGAAGAA
GCAAGAACATGAAGGAGCAAGCTTTAACGGAGCATCCA
CAGCACCGCTCTTTGAC3150
GTCAAAGAGCGGTGCTG3151
Non-polyposisTGCTTGCCTTAGATAGTCCAGAGAGTGGCTGGACAGAGGAAG3152
colorectal cancerATGGTCCCAAAGAAGGACTTGCTGAATACATTGTTGAGTTTCT
Leu607HisGAAGAAGAAGGCTGAGATGCTTGCAGACTATTTCTC
CTT-CATGAGAAATAGTCTGCAAGCATCTCAGCCTTCTTCTTCAGAAACT3153
CAACAATGTATTCAGCAAGTCCTTCTTTGGGACCATCTTCCTC
TGTCCAGCCACTCTCTGGACTATCTAAGGCAAGCA
AGAAGGACTTGCTGAAT3154
ATTCAGCAAGTCCTTCT3155
Non-polyposisACAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATT3156
colorectal cancerGTTGAGTTTCTGAAGAAGAAGGCTGAGATGCTTGCAGACTAT
Lys618TermTTCTCTTTGGAAATTGATGAGGTGTGACAGCCATTCT
AAG-TAGAGAATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGTC3157
TGCAAGCATCTCAGCCTTCTTCTTCAGAAACTCAACAATGTAT
TCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTGT
TGAAGAAGAAGGCTGAG3158
CTCAGCCTTCTTCTTCA3159
Non-polyposisCAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATTG3160
colorectal cancerTTGAGTTTCTGAAGAAGAAGGCTGAGATGCTTGCAGACTATTT
Lys618ThrCTCTTTGGAAATTGATGAGGTGTGACAGCCATTCTT
AAG-ACGAAGAATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGT3161
CTGCAAGCATCTCAGCCTTCTTCTTCAGAAACTCAACAATGTA
TTCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTG
GAAGAAGAAGGCTGAGA3162
TCTCAGCCTTCTTCTTC3163
Non-polyposisTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC3164
colorectal cancerTGCCTATCTTCATTCTTCGACTAGCCACTGAGGTCAGTGATCA
Arg659LeuAGCAGATACTAAGCATTTCGGTACATGCATGTGTGC
CGA-CTAGCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC3165
TGACCTCAGTGGCTAGTCGAAGAATGAAGATAGGCAGTCCCT
CCAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA
CATTCTTCGACTAGOCA3166
TGCCTAGTCGAACAATG3167
Non-polyposisTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC3168
colorectal cancerTGCCTATCTTCATTCTTCGACTAGCCACTGAGGTCAGTGATCA
Arg659ProAGCAGATACTAAGCATTTCGGTACATGCATGTGTGC
CGA-CCAGCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC3169
TGACCTCAGTGGCTAGTCGAAGAATGAAGATAGGCAGTCCCT
CCAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA
CATTCTTCGACTAGCCA3170
TGGCTAGTCGAAGAATG3171
Non-polyposisTTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGA3172
colorectal cancerCTGCCTATCTTCATTCTTCGACTAGCCACTGAGGTCAGTGATC
Arg659TermAAGCAGATACTAAGCATTTCGGTACATGCATGTGTG
CGA-TGACACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCACT3173
GACCTCAGTGGCTAGTCGAAGAATGAAGATAGGCAGTCCCTC
CAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTAA
TCATTCTTCGACTAGCC3174
GGCTAGTCGAAGAATGA3175
Non-polyposisTTGGACCAGGTGAATTGGGACGAAGAAAAGGAATGTTTTGAA3176
colorectal cancerAGCCTCAGTAAAGAATGCGCTATGTTCTATTCCATCCGGAAG
Ala681ThrCAGTACATATCTGAGGAGTCGACCCTCTCAGGCCAGC
GCT-ACTGCTGGCCTGAGAGGGTCGACTCCTCAGATATGTACTGCTTCC3177
GGATGGAATAGAACATAGCGCATTCTTTACTGAGGCTTTCAAA
ACATTCCTTTTCTTCGTCCCAATTCACCTGGTCCAA
AAGAATGCGCTATGTTC3178
GAACATAGCGCATTCTT3179
Non-polyposisAGGCTTATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGG3180
colorectal cancerCTCCATTCCAAACTCCTGGAAGTGGACTGTGGAACACATTGT
Trp7l2TermCTATAAAGCCTTGCGCTCACACATTCTGCCTCCTAA
TGG-TAGTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAGACAATG3181
TGTTCCACAGTCCACTTCCAGGAGTTTGGAATGGAGCCAGGC
ACTTCACTCTGGAAAACACATTAGATGTCATAAGCCT
AAACTCCTGGAAGTGGA3182
TCCACTTCCAGGAGTTT3183
Non-polyposisATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCAT3184
colorectal cancerTCCAAACTCCTGGAAGTGGACTGTGGAACACATTGTCTATAAA
Trp7l4TermGCCTTGCGCTCACACATTCTGCCTCCTAAACATTT
TGG-TAGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAG3185
ACAATGTGTTCCACAGTCCACTTCCAGGAGTTTGGAATGGAG
CCAGGCACTTCACTCTGGAAAACACATTAGATGTCAT
CTGGAAGTGGACTGTGG3186
CCACAGTCCACTTCCAG3187
Non-polyposisTGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATT3188
colorectal cancerCCAAACTCCTGGAAGTGGACTGTGGAACACATTGTCTATAAA
Trp7l4TermGCCTTGCGCTCACACATTCTGCCTCCTAAACATTTC
TGG-TGAGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATA3189
GACAATGTGTTCCACAGTCCACTTCCAGGAGTTTGGAATGGA
GCCAGGCACTTCACTCTGGAAAACACATTAGATGTCA
TGGAAGTGGACTGTGGA3190
TCCACAGTCCACTTCCA3191
Non-polyposisATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATTCCAA3192
colorectal cancerACTCCTGGAAGTGGACTGTGGAACACATTGTCTATAAAGCCTT
Val7l6MetGCGCTCACACATTCTGCCTCCTAAACATTTCACAG
GTG-ATGCTGTGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTT3193
TATAGACAATGTGTTCCACAGTCCACTTCCAGGAGTTTGGAAT
GGAGCCAGGCACTTCACTCTGGAAAACACATTAGAT
AGTGGACTGTGGAACAC3194
GTGTTCCACAGTCCACT3195
Non-polyposisGAGTGAAGTGCCTGGCTCCATTCCAAACTCCTGGAAGTGGAC3196
colorectal cancerTGTGGAACACATTTGTCTATAAAGCCTTGCGCTCACACATTCTG
Tyr72lTermCCTCCTAAACATTTCACAGAAGATGGAAATATCCTG
TAT-TAACAGGATATTTCCATCTTCTGTGAAATGTTTAGGAGGCAGAATG3197
TGTGAGCGCAAGGCTTTATAGACAATGTGTTCCACAGTCCAC
TTCCAGGAGTTTGGAATGGAGCCAGGCACTTCACTC
ATTGTCTATAAAGCCTT3198
AAGGCTTTATAGACAAT3199
Non-polyposisCTAAACATTTCACAGAAGATGGAAATATCCTGCAGCTTGCTAA3200
colorectal cancer CCTGCCTGATCTATACAAAGTCTTTGAGAGGTGTTAAATATGG
Lys75lArgTTATTTATGCACTGTGGGATGTGTTCTTCTTTCTC
AAA-AGAGAGAAAGAAGAACACATCCCACAGTGCATAAATAACCATATTT3201
AACACCTCTCAAAGACTTTGTATAGATCAGGCAGGTTAGCAAG
CTGCAGGATATTTCCATCTTCTGTGAAATGTTTAG
TCTATACAAAGTCTTTG3202
CAAAGACTTTGTATAGA3203
Non-polyposisACAGAAGATGGAAATATCCTGCAGCTTGCTAACCTGCCTGAT3204
colorectal cancerCTATACAAAGTCTTTGAGAGGTGTTAAATATGGTTATTTATGCA
Arg755TrpCTGTGGGATGTGTTCTTCTTTCTCTGTATTCCGAT
AGG-TGGATCGGAATACAGAGAAAGAAGAACACATCCCACAGTGCATAA3205
ATAACCATATTTAACACCTCTCAAAGACTTTGTATAGATCAGG
CAGGTTAGCAAGCTGCAGGATATTTCCATCTTCTGT
TCTTTGAGAGGTGTTAA3206
TTAACACCTCTCAAAGA3207
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Human Mismatch Repair—MSH2
[0143] The human MSH2 gene is homologous to the bacterial mutS gene, which is involved in mismatch repair. Mutations in the MSH2 gene have been identified in a variety of cancers, including, for example, ovarian tumors, colorectal cancer, endometrial cancer, uterine cancer. The attached table discloses the correcting oligonucleotide base sequences for the MSH2 oligonucleotides of the invention.
26TABLE 25
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MSH2 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting QilgosNO:
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Non polyposisTTTTCCACAAAAGACATTTATCAGGACCTCAACCGGTTGTTGA3208
colorectal cancerAAGGCAAAAAGGGAGAGCAGATGAATAGTGCTGTATTGCCAG
Gln252TermAAATGGAGAATCAGGTACATGGATTATAAATGTGAA
CAG-TAGTTCACATTTATAATCCATGTACCTGATTCTCCATTTCTGGCAAT3209
ACAGCACTATTCATCTGCTCTCCCTTTTTGCCTTTCAACAACC
GGTTGAGGTCCTGATAAATGTCTTTTGTGGAAAA
AGGGAGAGCAGATGAAT3210
ATTCATCTGCTCTCCCT3211
Non polyposisTCATCACTGTCTGCGGTAATCAAGTTTTTAGAACTCTTATCAG3212
colorectal cancerATGATTCCAACTTTGGACAGTTTGAACTGACTACTTTTGACTT
Gln288TermCAGCCAGTATATGAAATTGGATATTGCAGCAGTCA
GAG-TAGTGACTGCTGCAATATCCAATTTCATATACTGGCTGAAGTCAAA3213
AGTAGTCAGTTCAAACTGTCCAAAGTTGGAATCATCTGATAAG
AGTTCTAAAAACTTGATTACCGCAGACAGTGATGA
ACTTTGGACAGTTTGAA3214
TTCAAACTGTCCAAAGT3215
Non polyposisAACTTTGGACAGTTTGAACTGACTACTTTTGACTTCAGCCAGT3216
colorectal cancerATATGAAATTGGATATTGCAGCAGTCAGAGCCCTTAACCTTTT
Ala305ThrTCAGGTAAAAAAAAAAAAAAAAAAAAAAAAAAAGG
GCA-ACACCTTTTTTTTTTTTTTTTTTTTTTTTTTTACCTGAAAAAGGTTAAG3217
GGCTCTGACTGCTGCAATATCCAATTTCATATACTGGCTGAAG
TCAAAAGTAGTCAGTTCAAACTGTGCTCCAAAGTT
TGGATATTGCAGCAGTC3218
GACTGCTGCAATATCCA3219
Non polyposisAGCTTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCT3220
colorectal cancerGTTGAAGATACCACTGGCTCTCAGTCTCTGGCTGCCTTGCTG
Gly322AspAATAAGTGTAAAACCCCTCAAGGACAAAGACTTGT
GGC-GACACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCAAGG3221
CAGCCAGAGACTGAGAGCCAGTGGTATCTTCAACAGAACCCT
AGTAAACAAAAAATAAAATAGAAAGAATGGCAAGCT
TACCACTGGCTCTCAGT3222
ACTGAGAGCCAGTGGTA3223
Non polyposisTTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCTGTTG3224
colorectal cancerAAGATACCACTGGCTCTCAGTCTCTGGCTGCCTTGCTGAATA
Ser323CysAGTGTAAAACCCCTCAAGGACAAAGACTTGTTAA
TCT-TGTTTAACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCA3225
AGGCAGCCAGAGACTGAGAGCCAGTGGTATCTTCAACAGAAC
CCTAGTAAACAAAAAATAAAATAGAAAGAATGGCAA
CACTGGCTCTCAGTCTC3226
GAGACTGAGAGCCAGTG3227
Non polyposisGTGGAAGCTTTTGTAGAAGATGCAGAATTGAGGCAGACTTTA3228
colorectal cancerCAAGAAGATTTACTTCGTCGATTCCCAGATCTTAACCGACTTG
Arg383TermCCAAGAAGTTTCAAAGACAAGCAGCAAACTTACAAG
CGA-TGACTTGTAAGTTTGCTGCTTGTCTTTGAAACTTCTTGGCAAGTCG3229
GTTAAGATCTGGGAATCGACGAAGTAAATCTTCTTGTAAAGTC
TGCCTCAATTCTGCATCTTCTACAAAAGCTTCCAC
TACTTCGTCGATTCCCA3230
TGGGAATCGACGAAGTA3231
Non polyposisCAAGAAGATTTACTTCGTCGATTCCCAGATCTTAACCGACTTG3232
colorectal cancerCCAAGAAGTTTCAAAGACAAGCAGCAAACTTACAAGATTGTTA
Gln397TermCCGACTCTATCAGGGTATAAATCAACTACCTAATG
CAA-TAACATTAGGTAGTTGATTTATACCCTGATAGAGTCGGTAACAATC3233
TTGTAAGTTTGCTGCTTGTCTTTGAAACTTCTTGGCAAGTCGG
TTAAGATCTGGGAATCGACGAAGTAAATCTTCTTG
TTCAAAGACAAGCAGCA3234
TGCTGCTTGTCTTTGAA3235
Non polyposisGATCTTAACCGACTTGCCAAGAAGTTTCAAAGACAAGCAGCA3236
colorectal cancerAACTTACAAGATTGTTACCGACTCTATCAGGGTATAAATCAAC
Arg406TermTACCTAATGTTATACAGGCTCTGGAAAAACATGAAG
CGA-TGACTTCATGTTTTTCCAGAGCCTGTATAACATTAGGTAGTTGATTT 3237
ATACCCTGATAGAGTCGGTAACAATCTTGTAAGTTTGCTGCTT
GTCTTTGAAACTTCTTGGCAAGTCGGTTAAGATC
ATTGTTACCGACTCTAT3238
ATAGAGTCGGTAACAAT3239
Non polyposisGCAAACTTACAAGATTGTTACCGACTCTATCAGGGTATAAATC3240
colorectal cancerAACTACCTAATGTTATACAGGCTCTGGAAAAACATGAAGGTAA
Gln419TermCAAGTGATTTTGTTTTTTTGTTTTCCTTCAACTCA
GAG-TAGTGAGTTGAAGGAAAACAAAAAAACAAAATCACTTGTTACCTTC3241
ATGTTTTTCCAGAGCCTGTATAACATTAGGTAGTTGATTTATAC
CCTGATAGAGTCGGTAACAATCTTGTAAGTTTGC
ATGTTATACAGGCTCTG3242
CAGAGCCTGTATAACAT3243
Non polyposisTATTCTGTAAAATGAGATCTTTTTATTTGTTTGTTTTACTACTTT3244
colorectal cancerCTTTTAGGAAAACACCAGAAATTATTGTTGGCAGTTTTTGTGA
Gln429TermCTCCTCTTACTGATCTTCGTTCTGACTTCTCCA
GAG-TAGTGGAGAAGTCAGAACGAAGATGAGTAAGAGGAGTCACAAAAA3245
CTGCCAACAATAATTTCTGGTGTTTTCCTAAAAGAAAGTAGTA
AAACAAACAAATAAAAAGATCTCATTTTACAGAATA
CAAAACACCAGAAATTA3246
TAATTTCTGGTGTTTTC3247
Non polyposisCTCCTCTTACTGATCTTCGTTCTGACTTCTCCAAGTTTCAGGA3248
colorectal cancerAATGATAGAAACAACTTTAGATATGGATCAGGTATGCAATATA
Leu458TermCTTTTTAATTTAAGCAGTAGTTATTTTTAAAAAGC
TTA-TGAGCTTTTTAAAAATAACTACTGCTTAAATTAAAAAGTATATTGCA3249
TACCTGATCCATATCTAAAGTTGTTTCTATCATTTCCTGAAACT
TGGAGAAGTCAGAACGAAGATCAGTAAGAGGAG
AACAACTTTAGATATGG3250
CCATATCTAAAGTTGTT3251
Non polyposisTTTCTTCTTGATTATCAAGGCTTGGACCCTGGCAAACAGATTA3252
colorectal cancerAACTGGATTCCAGTGCACAGTTTGGATATTACTTTCGTGTAAC
Gln518TermCTGTAAGGAAGAAAAAGTCCTTCGTAACAATAAAA
CAG-TAGTTTTATTGTTACGAAGGACTTTTTCTTCCTTACAGGTTACACGA3253
AAGTAATATCCAAACTGTGCACTGGAATCCAGTTTAATCTGTT
TGCCAGGGTCCAAGCCTTGATAATCAAGAAGAAA
CCAGTGCACAGTTTGGA3254
TCCAAACTGTGCACTGG3255
Non polyposisGCTTGGACCCTGGCAAACAGATTAAACTGGATTCCAGTGCAC3256
colorectal cancerAGTTTGGATATTACTTTCGTGTAACCTGTAAGGAAGAAAAAGT
Arg524ProCCTTCGTAACAATAAAAACTTTAGTACTGTAGATAT
CGT-CCTATATCTACAGTACTAAAGTTTTTATTGTTACGAAGGACTTTTTC3257
TTCCTTACAGGTTACACGAAAGTAATATCCAAACTGTGCACTG
GAATCCAGTTTAATCTGTTTGCCAGGGTCCAAGC
TTACTTTCGTGTAACCT3258
AGGTTACACGAAAGTAA3259
Non polyposisTTAATATTTTTAATAAAACTGTTATTTCGATTTGCAGCAAATTGA3260
colorectal cancerCTTCTTTAAATGAAGAGTATACCAAAAATAAAACAGAATATGAA
Glu562ValGAAGCCCAGGATGCCATTGTTAAAGAAATTGT
GAG-GTGACAATTTCTTTAACAATGGCATCCTGGGCTTCTTCATATTCTGT3261
TTTATTTTTGGTATACTCTTCATTTAAAGAAGTCAATTTGCTGC
AAATCGAAATAACAGTTTTATTAAAAATATTAA
AAATGAAGAGTATACCA3262
TGGTATACTCTTCATTT3263
GliomaAATGAAGAGTATACCAAAAATAAAACAGAATATGAAGAAGCCC3264
Glu580TermAGGATGCCATTGTTAAAGAAATTGTCAATATTTCTTCAGGTAAA
GAA-TAACTTAATAGAACTAATAATGTTCTGAATGTCACCT
AGGTGACATTCAGAACATTATTAGTTCTATTAAGTTTACCTGAA3265
GAAATATTGACAATTTCTTTAACAATGGCATCCTGGGCTTCTT
CATATTCTGTTTTATTTTTGGTATACTCTTCATT
TTGTTAAAGAAATTGTC3266
GACAATTTCTTTAACAA3267
Non polyposisTGTTTTTATTTTTATACAGGCTATGTAGAACCAATGCAGACACT3268
colorectal cancerCAATGATGTGTTAGCTCAGCTAGATGCTGTTGTCAGCTTTGCT
Cln601TermCACGTGTCAAATGGAGCACCTGTTCCATATGTAC
GAG-TAGGTACATATGGAACAGGTGCTCCATTTGACACGTGAGCAAAGC3269
TGACAACAGCATCTAGCTGAGCTAACACATCATTGAGTGTCTG
CATTGGTTCTACATAGCCTGTATAAAAATAAAAACA
TGTTAGCTCAGCTAGAT3270
ATCTAGCTGAGCTAACA3271
Non polyposisAGCTCAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAAT3272
colorectal cancerGGAGCACCTGTTCCATATGTACGACCAGCCATTTTGGAGAAA
Tyr619TermGGACAAGGAAGAATTATATTAAAAGCATCCAGGCAT
TAT-TAGATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTCTCCA3273
AAATGGCTGGTCGTACATATGGAACAGGTGCTCCATTTGACA
CGTGAGCAAAGCTGACAACAGCATCTAGCTGAGCT
GTTCCATATGTACGACC3274
GGTCGTACATATGGAAC3275
Non polyposisCAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAATGGA3276
colorectal cancerGCACCTGTTCCATATGTACGACCAGCCATTTTGGAGAAAGGA
Arg621TermCAAGGAAGAATTATATTAAAAGCATCCAGGCATGCTT
CGA-TGAAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTC3277
TCCAAAATGGCTGGTCGTACATATGGAACAGGTGCTCCATTT
GACACGTGAGCAAAGCTGACAACAGCATCTAGCTG
CATATGTACGACCAGCC3278
GGCTGGTCGTACATATG3279
Non polyposisTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAATGGAGCAC3280
colorectal cancerCTGTTCCATATGTACGACCAGCCATTTTGGAGAAAGGACAAG
Pro622LeuGAAGAATTATATTAAAAGCATCCAGGCATGCTTGTGT
CCA-CTAACACAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTC3281
CTTTCTCCAAAATGGCTGGTCGTACATATGGAACAGGTGCTC
CATTTGACACGTGAGCAAAGCTGACAACAGCATCTA
TGTACGACCAGCCATTT3282
AAATGGCTGGTCGTACA3283
Non polyposisCCTGTTCCATATGTACGACCAGCCATTTTGGAGAAAGGACAA3284
colorectal cancerGGAAGAATTATATTAAAAGCATCCAGGCATGCTTGTGTTGAAG
Ala636ProTTCAAGATGAAATTGCATTTATTCCTAATGACGTAT
GCA-CCAATACGTCATTAGGAATAAATGCAATTTCATCTTGAACTTCAACA3285
CAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTT
CTCCAAAATGGCTGGTCGTACATATGGAACAGG
TATTAAAAGCATCCAGG3286
CCTGGATGCTTTTAATA3287
Non polyposisATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAATTA3288
colorectal cancerTATTAAAAGCATCCAGGCATGCTTGTGTTGAAGTTCAAGATGA
His639ArgAATTGCATTTATTCCTAATGACGTATACTTTGAAAA
CAT-CGTTTTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTG3289
AACTTCAACACAAGCATGCCTGGATGCTTTTAATATAATTCTTC
CTTGTCCTTTCTCCAAAATGGCTGGTCGTACAT
ATCCAGGCATGCTTGTG3290
CACAAGCATGCCTGGAT3291
Non polyposisTATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAAT3292
colorectal cancerATATTAAAAGCATCCAGGCATGCTTGTGTTGAAGTTCAAGATG
His639TyrAAATTGCATTTATTCCTAATGACGTATACTTTGAAA
CAT-TATTTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTGA3293
ACTTCAACACAAGCATGCCTGGATGCTTTTAATATAATTCTTC
CTTGTCCTTTCTCCAAAATGGCTGGTCGTACATA
CATCCAGGCATGCTTGT3294
ACAAGCATGCCTGGATG3295
Non polyposisAAAGGACAAGGAAGAATTATATTAAAAGCATCCAGGCATGCTT3296
colorectal cancerGTGTTGAAGTTCAAGATGAAATTGCATTTATTCCTAATGACGT
Glu647LysATACTTTGAAAAAGATAAACAGATGTTCCACATCA
GAA-AAATGATGTGGAACATCTGTTTATCTTTTTCAAAGTATACGTCATTA3297
GGAATAAATGCAATTTCATCTTGAACTTCAACACAAGCATGCC
TGGATGCTTTTAATATAATTCTTCCTTGTCCTTT
TTCAAGATGAAATTGCA3298
TGCAATTTCATCTTGAA3299
Non polyposisATCCAGGCATGCTTGTGTTGAAGTTCAAGATGAAATTGCATTT3300
colorectal cancerATTCCTAATGACGTATACTTTGAAAAAGATAAACAGATGTCCA
Tyr656TermCATCATTACTGGTAAAAAACCTGGTTTTTGGGCT
TAC-TAGAGCCCAAAAACCAGGTTTTTTACCAGTAATGATGTGGAACATC3301
TGTTTATCTTTTTCAAAGTATACGTCATTAGGAATAAATGCAAT
TTCATCTTGAACTTCAACACAAGCATGCCTGGAT
GACGTATACTTTGAAAA3302
TTTTCAAAGTATACGTC3303
Non polyposisGAAAGAAGTTTAAAATCTTGCTTTCTGATATAATTTGTTTTGTA3304
colorectal cancerGGCCCCAATATGGGAGGTAAATCAACATATATTCGACAAACT
Gly674AspGGGGTGATAGTACTCATGGCCCAAATTGGGTGTTT
GGT-GATAAACACCCAATTTGGGCCATGAGTACTATCACCCCAGTTTGTC3305
GAATATATGTTGATTTACCTCCCATATTGGGGCCTACAAAACA
AATTATATCAGAAAGCAAGATTTTAAACTTCTTTC
TATGGGAGGTAAATCAA3306
TTGATTTACCTCCCATA3307
Non polyposisTTGCTTTCTGATATAATTTGTTTTGTAGGCCCCAATATGGGAG3308
colorectal cancerGTAAATCAACATATATTCGACAAACTGGGGTGATAGTACTCAT
Arg680TermGGCCCAAATTGGGTGTTTTGTGCCATGTGAGTCAG
CGA-TGACTGACTCACATGGCACAAAACACCCAATTTGGGCCATGAGTA3309
CTATCACCCCAGTTTGTCGAATATATGTTGATTTACCTCCCAT
ATTGGGGCCTACAAAACAAATTATATCAGAAAGCAA
CATATATTCGACAAACT3310
AGTTTGTCGAATATATG3311
Non polyposisATGGGAGGTAAATCAACATATATTCGACAAACTGGGGTGATA3312
colorectal cancerGTACTCATGGCCCAAATTGGGTGTTTTGTGCCATGTGAGTCA
Gly692ArgGCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGAG
GGG-CGGCTCGGGCTAAGATGCAGTCCACAATGGACACTTCTGCTGACT3313
CACATGGCACAAAACACCCAATTTGGGCCATGAGTACTATCA
CCCCAGTTTGTCGAATATATGTTGATTTACCTCCCAT
CCCAAATTGGGTGTTTT3314
AAAACACCCAATTTGGG3315
Non polyposisACATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAA3316
colorectal cancerTTGGGTGTTTTGTGCCATGTGAGTCAGCAGAAGTGTCCATTG
Cys697ArgTGGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACA
TGT-CGTTGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATGG3317
ACACTTCTGCTGACTCACATGGCACAAAACACCCAATTTGGG
CCATGAGTACTATCACCCCAGTTTGTCGAATATATGT
TTGTGCCATGTGAGTCA3318
TGACTCACATGGCACAA3319
Non polyposisCATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAAT3320
colorectal cancerTGGGTGTTTTGTGCCATGTGAGTCAGCAGAAGTGTCCATTGT
Cys697PheGGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACAG
TGT-TTTCTGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATG3321
GACACTTCTGCTGACTCACATGGCACAAAACACCCAATTTGG
GCCATGAGTACTATCACCCCAGTTTGTCGAATATATG
TGTGCCATGTGAGTCAG3322
CTGACTCACATGGCACA3323
Non polyposisGAGTCAGCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGA3324
colorectal cancerGTAGGGGCTGGTGACAGTCAATTGAAAGGAGTCTCCACGTTC
Gln718TermATGGCTGAAATGTTGGAAACTGCTTCTATCCTCAGGT
CAA-TAAACCTGAGGATAGAAGCAGTTTCCAACATTTCAGCCATGAACG3325
TGGAGACTCCTTTCAATTGACTGTCACCAGCCCCTACTCGGG
CTAAGATGCAGTCCACAATGGACACTTCTGCTGACTC
GTGACAGTCAATTGAAA3326
TTTCAATTGACTGTCAC3327
Non polyposisCCAATCAGATACCAACTGTTAATAATCTACATGTCACAGCACT3328
colorectal cancerCACCACTGAAGAGACCTTAACTATGCTTTATCAGGTGAAGAAA
Leu811TermGGTATGTACTATTGGAGTACTCTAAATTCAGAACT
TTA-TGAAGTTCTGAATTTAGAGTACTCCAATAGTACATACCTTTCTTCAC3329
CTGATAAAGCATAGTTAAGGTCTCTTCAGTGGTGAGTGCTGT
GACATGTAGATTATTAACAGTTGGTATCTGATTGG
AGAGACCTTAACTATGC3330
GCATAGTTAAGGTCTCT3331
Non polyposisTTCCCCAAATTTCTTATAGGTGTCTGTGATCAAAGTTTTGGGA3332
colorectal cancerTTCATGTTGCAGAGCTTGCTAATTTCCCTAAGCATGTAATAGA
Ala834ThrGTGTGCTAAACAGAAAGCCCTGGAACTTGAGGAGT
GCT-ACTACTCCTCAAGTTCCAGGGCTTTCTGTTTAGCACACTCTATTAC3333
ATGCTTAGGGAAATTAGCAAGCTCTGCAACATGAATCCCAAAA
CTTTGATCACAGACACCTATAAGAAATTTGGGGAA
CAGAGCTTGCTAATTTC3334
GAAATTAGCAAGCTCTG3335
Non polyposisATAGAGTGTGCTAAACAGAAAGCCCTGGAACTTGAGGAGTT3336
colorectal cancerCAGTATATTGGAGAATCGCAAGGATATGATATCATGGAACCAG
Gln861TermCAGCAAAGAAGTGCTATCTGGAAAGAGAGGTTTGTC
CAA-TAAGACAAACCTCTCTTTCCAGATAGCACTTCTTTGCTGCTGGTTC3337
CATGATATCATATCCTTGCGATTCTCCAATATACTGAAACTCCT
CAAGTTCCAGGGCTTTCTGTTTAGCACACTCTAT
GAGAATCGCAAGGATAT3338
ATATCCTTGCGATTCTC3339
Non polyposisAGGAGTTCCTGTCCAAGGTGAAACAAATGCCCTTTACTGAAAT3340
colorectal cancerGTCAGAAGAAAACATCACAATAAAGTTAAAACAGCTAAAAGCT
Thr905ArgGAAGTAATAGCAAAGAATAATAGCTTTGTAAATGA
ACA-AGATCATTTACAAAGCTATTATTCTTTGCTATTACTTCAGCTTTAG3341
CTGTTTTAACTTTATTGTGATGTTTTCTTCTGACATTTCAGTAA
AGGGCATTTGTTTCACCTTGGACAGGAACTCCT
AAACATCACAATAAAGT3342
ACTTTATTGTGATGTTT3343
|
Human Mismatch Repair—MSH6
[0144] The human MSH6 gene is homologous to the bacterial mutS gene, which is involved in mismatch repair. Mutations in the MSH6 gene have been identified in a variety of cancers, including particularly hereditary nonpolyposis colorectal cancer. The attached table discloses the correcting oligonucleotide base sequences for the MSH6 oligonucleotides of the invention.
27TABLE 26
|
|
MSH6 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Non-polyposisGGAAATCAGTCCGTGTTCATGTACAGTTTTTTGATGACAGCCC3344
colorectal cancerAACAAGGGGCTGGGTTAGCAAAAGGCTTTTAAAGCCATATAC
Ser441IleAGGTAAGAGTCACTACTGCCATGTGTGTGTGTTTGT
AGC-ATCACAAACACACACACATGGCAGTAGTGACTCTTACCTGTATATG3345
GCTTTAAAAGCCTTTTGCTAACCCAGCCCCTTGTTGGGCTGT
CATCAAAAAACTGTACATGAACACGGACTGATTTCC
CTGGGTTAGCAAAAGGC3346
GCCTTTTGCTAACCCAG3347
Endometrial cancerCGTGAGCCTCTGCACCCGGCCCTTATTGTTTATAAATACATTT3348
Ser156TermCTTTCTAGGTTCAAAATCAAAGGAAGCCCAGAAGGGAGGTCA
TCA-TGATTTTTACAGTGCAAAGCCTGAAATACTGAGAGCAAT
ATTGCTCTCAGTATTTCAGGCTTTGCACTGTAAAAATGACCTC3349
CCTTCTGGGCTTCCTTTGATTTTGAACCTAGAAAGAAATGTAT
TTATAAACAATAAGGGCCGGGTGCAGAGGCTCACG
TTCAAAATCAAAGGAAG3350
CTTCCTTTGATTTTGAA3351
Early onset color-TTCCAAATTTTGATTTGTTTTTAAATACTCTTTCCTTGCCTGGC3352
ectal cancerAGGTAGGCACAACTTACGTAACAGATAAGAGTGAAGAAGATA
Tyr214TermATGAAATTGAGAGTGAAGAGGAAGTACAGCCTAAG
TAC-TAGCTTAGGCTGTACTTCCTCTTCACTCTCAATTTCATTATCTTCTT3353
CACTCTTATCTGTTACGTAAGTTGTGCCTACCTGCCAGGCAA
GGAAAGAGTATTTAAAAACAAATCAAAATTTGGAA
ACAACTTACGTAACAGA3354
TCTGTTACGTAAGTTGT3355
Endometrial cancerGAAGAGGAAGTACAGCCTAAGACACAAGGATCTAGGCGAAGT3356
Arg248TermAGCCGCCAAATAAAAAAACGAAGGGTCATATCAGATTCTGAG
CGA-TGAAGTGACATTGGTGGCTCTGATGTGGAATTTAAGCCAG
CTGGCTTAAATTCCACATCAGAGCCACCAATGTCACTCTCAGA3357
ATCTGATATGACCCTTCGTTTTTTTATTTGGCGGCTACTTCGC
CTAGATCCTTGTGTCTTAGGCTGTACTTCCTCTTC
TAAAAAAACGAAGGGTC3358
GACCCTTCGTTTTTTTA3359
Colorectal cancerTTAAGCCAGACACTAAGGAGGAAGGAAGCAGTGATGAAATAA3360
Ser285IleGCAGTGGAGTGGGGGATAGTGAGAGTGAAGGCCTGAACAGC
AGT-ATTCCTGTCAAAGTTGCTCGAAAGCGGAAGAGAATGGTGAC
GTCACCATTCTCTTCCGCTTTCGAGCAACTTTGACAGGGCTG3361
TTCAGGCCTTCACTCTCACTATCCCCCACTCCACTGCTTATTT
CATCACTGCTTCCTTCCTCCTTAGTGTCTGGCTTAA
GGGGGATAGTGAGAGTG3362
CACTCTCACTATCCCCC3363
Colorectal cancerGAGGAAGATTCTTCTGGCCATACTCGTGCATATGGTGTGTGC3364
Gly566ArgTTTGTTGATACTTCACTGGGAAAGTTTTTCATAGGTCAGTTTTC
GGA-AGAAGATGATCGCCATTGTTCGAGATTTAGGACTCTAG
CTAGAGTCCTAAATCTCGAACAATGGCGATCATCTGAAAACTG3365
ACCTATGAAAAACTTTCCCAGTGAAGTATCAACAAAGCACACA
CCATATGCACGAGTATGGCCAGAAGAATCTTCCTC
CTTCACTGGGAAAGTTT3366
AAACTTTCCCAGTGAAG3367
Non-polyposisGAATTGGCCCTCTCTGCTCTAGGTGGTTGTGTCTTCTACCTC3368
colorectal cancerAAAAAATGCCTTATTGATCAGGAGCTTTTATCAATGGCTAATTT
Gln698GluTGAAGAATATATTCCCTTGGATTCTGACACAGTCA
CAG-GAGTGACTGTGTCAGAATCCAAGGGAATATATTCTTCAAAATTAGC3369
CATTGATAAAAGCTCCTGATCAATAAGGCATTTTTTGAGGTAG
AAGACACAACCACCTAGAGCAGAGAGGGCCAATTC
TTATTGATCAGGAGCTT3370
AAGCTCCTGATCAATAA3371
Endometrial cancerCCCTTGGATTCTGACACAGTCAGCACTACAAGATCTGGTGCT3372
Gln731TermATCTTCACCAAAGCCTATCAACGAATGGTGCTAGATGCAGTG
CAA-TAAACATTAAACAACTTGGAGATTTTTCTGAATGGAACAA
TTGTTCCATTCAGAAAAATCTCCAAGTTGTTTTAATGTCACTGCA3373
TCTAGCACCATTCGTTGATAGGCTTTGGTGAAGATAGCACCA
GATCTTGTAGTGCTGACTGTGTCAGAATCCAAGGG
AAGCCTATCAACGAATG3374
CATTCGTTGATAGGCTT3375
Colorectal cancerGCCCCACTCTGTAACCATTATGCTATTAATGATCGTCTAGATG3376
Val800LeuCCATAGAAGACCTCATGGTTGTGCCTGACAAAATCTCCGAAG
GTT-CTTTTGTAGAGCTTCTAAAGAAGCTTCCAGATCTTGAGA
TCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTACAACTTCGGA3377
GATTTTGTCAGGCACAACCATGAGGTCTTCTATGGCATCTAGA
CGATCATTAATAGCATAATGGTTACAGAGTGGGGC
ACCTCATGGTTGTGCCT3378
AGGCACAACCATGAGGT3379
Colorectal cancerGTAACCATTATGCTATTAATGATCGTCTAGATGCCATAGAAGA3380
Asp803GlyCCTCATGGTTGTGCCTGACAAAATCTCCGAAGTTGTAGAGCT
GAC-GGCTCTAAAGAAGCTTCCAGATCTTGAGAGGCTACTCAG
CTGAGTAGCCTCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTA3381
CAACTTCGGAGATTTTGTCAGGCACAACCATGAGGTCTTCTAT
GGCATCTAGACGATCATTAATAGCATAATGGTTAC
TGTGCCTGACAAAATCT3382
AGATTTTGTCAGGCACA3383
Non-polyposisCTCCCCTGAAGAGTGAGAACCACCCAGACAGCAGGGCTATAA3384
colorectal cancerTGTATGAAGAAACTACATACAGCAAGAAGAAGATTATTGATTT
Tyr850CysTCTTTCTGCTCTGGAAGGATTCAAAGTAATGTGTAA
TAC-TGCTTACACATTACTTTGAATCCTTCCAGAGCAGAAAGAAAATCAA3385
TAATCTTCTTCTTGCTGTATGTAGTTTCTTCATACATTATAGCC
CTGCTGTCTGGGTGGTTCTGACTCTTCAGGGGAG
AACTACATACAGCAAGA3386
TCTTGCTGTATGTAGTT3387
Colorectal cancerTATAGTCGAGGGGGTGATGGTCCTATGTGTCGCCCAGTAATT3388
Pro1087ThrCTGTTGCCGGAAGATACCCCCCCCTTCTTAGAGCTTAAAGGA
CCC-ACCTCACGCCATCCTTGCATTACGAAGACTTTTTTTGGAG
CTCCAAAAAAAGTCTTCGTAATGCAAGGATGGCGTGATCCTTT3389
AAGCTCTAAGAAGGGGGGGGTATCTTCCGGCAACAGAATTAC
TGGGCGACACATAGGACCATCACCCCCTCGACTATA
AAGATACCCCCCCCTTC3390
GAAGGGGGGGGTATCTT3391
Non-polyposisACTATAAAATGTCGTACATTATTTTCAACTCACTACCATTCATT3392
colorectal cancerAGTAGAAGATTATTCTCAAAATGTTGCTGTGCGCCTAGGACAT
Gln1258TermATGGTATGTGCAAATTGTTTTTTTCCACAAATTC
CAA-TAAGAATTTGTGGAAAAAAACAATTTGCACATACCATATGTCCTAG3393
GCGCACAGCAACATTTTGAGAATAATCTTCTACTAATGAATGG
TAGTGAGTTGAAAATAATGTACGACATTTTATAGT
ATTATTCTCAAAATGTT3394
AACATTTTGAGAATAAT3395
|
Hyperlipidemia—APOE
[0145] Hyperlipidemia is the abnormal elevation of plasma cholesterol and/or triglyceride levels and it is one of the most common diseased. The human apolipoprotein E protein is involved in the transport of endogenous lipids and appears to be crucial for both the direct removal of cholesterol-rich LDL from plasma and conversion of IDL particles to LDL particles. Individuals who either lack apolipoprotein E or who are homozygous for particular alleies of apoE may have have a condition known as dysbetaiipoproteinemia, which is characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis.
[0146] In a comprehensive review of apoE variants, de Knijff et al., Hum. Mutat. 4:178-194 (1994) found that 30 variants had been characterized, including the most common variant, apoE3. To that time, 14 apoE variants had been found to be associated with familial dysbetalipoproteinemia. The attached table discloses the correcting oligonucleotide base sequences for the APOE oligonucleotides of the invention.
28TABLE 27
|
|
APOE Mutations and Genome-Correcting Oligos
ClinicaI Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Apolipoprotein ETTGTTCCACACAGGATGCCAGGCCAAGGTGGAGCAAGCGGT3396
Glu13LysGGAGACAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAG
cGAG-AAGTGGCAGAGCGGCCAGCGCTGGGAACTGGCACTGGGTCGCT
AGCGACCCAGTGCCAGTTCCCAGCGCTGGCCGCTCTGCCAC3397
TCGGTCTGCTGGCGCAGCTCGGGCTCCGGCTCTGTCTCCAC
CGCTTGCTCCACCTTGGCCTGGCATCCTGTGTGGAACAA
CGGAGCCCGAGCTGCGC3398
GCGCAGCTCGGGCTCCG3399
Apolipoprotein ECAAGGTGGAGCAAGCGGTGGAGACAGAGCCGGAGCCCGAG3400
Trp20TermCTGCGCCAGCAGACCGAGTGGCAGAGCGGCCAGCGCTGGG
TGGc-TGAAACTGGCACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTG
CACCCAGCGCAGGTAATCCCAAAAGCGACCCAGTGCCAGTT3401
CCCAGCGCTGGCCGCTCTGCCACTCGGTCTGCTGGCGCAGC
TCGGGCTCCGGCTCTGTCTCCACCGCTTGCTCCACCTTG
ACCGAGTGGCAGAGCGG3402
CCGCTCTGCCACTCGGT3403
Apolipoprotein ECAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAGTGGCA3404
Leu28ProGAGCGGCCAGCGCTGGGAACTGGCACTGGGTCGCTTTTGGG
CTG-CCGATTACCTGCGCTGGGTGCAGACACTGTCTGAGCAGGTGCA
TGCACCTGCTCAGACAGTGTCTGCACCCAGCGCAGGTAATCC3405
CAAAAGCGACCCAGTGCCAGTTCCCAGCGCTGGCCGCTCTG
CCACTCGGTCTGCTGGCGCAGCTCGGGCTCCGGCTCTG
CTGGGAACTGGCACTGG3406
CCAGTGCCAGTTCCCAG3407
Apolipoprotein ECGGCTGTCCAAGGAGCTGCAGGCGGCGCAGGCCCGGCTGG3408
Cys112ArgGCGCGGACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTA
gTGC-CGCCCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAGCACCGAG
G
CCTCGGTGCTCTGGCCGAGCATGGCCTGCACCTCGCCGCGG3409
TACTGCACCAGGCGGCCGCACACGTCCTCCATGTCCGCGCC
CAGCCGGGCCTGCGCCGCCTGCAGCTCCTTGGACAGCCG
AGGACGTGTGCGGCCGC3410
GCGGCCGCACACGTCCT3411
Apolipoprotein EACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTACCGCGG3412
Gly127AspCGAGGTGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTG
GGC-GACCGGGTGCGCCTCGCCTCCCACCTGCGCAAGCTGCGTAAGCG
CGCTTACGCAGCTTGCGCAGGTGGGAGGCGAGGCGCACCC3413
GCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCACCTCG
CCGCGGTACTGCACCAGGCGGCCGCACACGTCCTCCATGT
CATGCTCGGCCAGAGCA3414
TGCTCTGGCCGAGCATG3415
Apolipoprotein EGTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA3416
Arg136CysGCACCGAGGAGCTGCGGGTGCGCCTCGCCTCCCACCTGCG
gCGC-TGCCAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGC
GCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTTG3417
CGCAGGTGGGAGGCGAGGCGCACCCGCAGCTCCTCGGTGC
TCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCAC
TGCGGGTGCGCCTCGCC3418
GGCGAGGCGCACCCGCA3419
Apolipoprotein ETGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAG3420
Arg136HisCACCGAGGAGCTGCGGGTGCGCCTCGCCTCCCACCTGCGC
CGC-CACAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGCA
TGCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTT3421
GCGCAGGTGGGAGGCGAGGCGCACCCGCAGCTCCTCGGTG
CTCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCA
GCGGGTGCGCCTCGCCT3422
AGGCGAGGCGCACCCGC3423
Apolipoprotein EGTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA3424
Arg136SerGCACCGAGGAGCTGCGGGTGCGCCTCGCCTCCCACCTGCG
gCGC-AGCCAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGC
GCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTTG3425
CGCAGGTGGGAGGCGAGGCGCACCCGCAGCTCCTCGGTGC
TCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCAC
TGCGGGTGCGCCTCGCC3426
GGCGAGGCGCACCCGCA3427
Apolipoprotein EGTGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGG3428
Arg142CysTGCGCCTCGCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTC
gCGC-TGCCTCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGT
ACACTGCCAGGCGCTTCTGCAGGTCATCGGCATCGCGGAGG3429
AGCCGCTTACGCAGCTTGCGCAGGTGGGAGGCGAGGCGCA
CCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCAC
CCCACCTGCGCAAGCTG3430
CAGCTTGCGCAGGTGGG3431
Apolipoprotein ETGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGGT3432
Arg142LeuGCGCCTCGCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCC
CGC-CTCTCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGTA
TACACTGCCAGGCGCTTCTGCAGGTCATCGGCATCGCGGAG3433
GAGCCGCTTACGCAGCTTGCGCAGGTGGGAGGCGAGGCGC
ACCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCA
CCACCTGCGCAAGCTGC3434
GCAGCTTGCGCAGGTGG3435
Apolipoprotein EATGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCG3436
Arg145CysCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGAT
gCGT-TGTGCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCG
CGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGCA3437
TCGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGAGG
CGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAGCAT
GCAAGCTGCGTAAGCGG3438
CCGCTTACGCAGCTTGC3439
Apolipoprotein ETGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGC3440
Arg145ProCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGATG
CGT-CCTCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGG
CCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGC3441
ATCGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGAG
GCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAGCA
CAAGCTGCGTAAGCGGC3442
GCCGCTTACGCAGCTTG3443
Apolipoprotein ECTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT3444
Lys146GluCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGATGCC
tAAG-CAGGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGG
CCCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG3445
GCATCGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGA
GGCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAG
AGCTGCGTAAGCGGCTC3446
GAGCCGCTTACGCAGCT3447
Apolipoprotein ECTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT3448
Lys146GluCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGATGCC
tAAG-GAGGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGG
CCCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG3449
GCATCGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGA
GGCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAG
AGCTGCGTAAGCGGCTC3450
GAGCCGCTTACGCAGCT3451
Apolipoprotein EGCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGA3452
Arg158CysTGCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCG
gCGC-TGCGGGCCCGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCC
GGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGCGGGCCCC3453
GGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGCAT
CGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGAGGC
TGCAGAAGCGCCTGGCA3454
TGCCAGGCGCTTCTGCA3455
Apolipoprotein ECGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCCGCGAGC3456
Gln187GluGCCTGGGGCCCCTGGTGGAACAGGGCCGCGTGCGGGCCGC
aCAG-GAGCACTGTGGGCTCCCTGGCCGGCCAGCCGCTACAGGAGCGG
G
CCCGCTCCTGTAGCGGCTGGCCGGCCAGGGAGCCCACAGT 3457
GGCGGCCCGCACGCGGCCCTGTTCCACCAGGGGCCCCAGG
CGCTCGCGGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGC
G
TGGTGGAACAGGGCCGC3458
GCGGCCCTGTTCCACCA3459
Apolipoprotein ETGCGGGCCGCCACTGTGGGCTCCCTGGCCGGCCAGCCGCT3460
Trp210TermACAGGAGCGGGCCCAGGCCTGGGGCGAGCGGCTGCGCGC
TGG-TAGGCGGATGGAGGAGATGGGCAGCCGGACCCGCGACCGCCTG
GA
TCCAGGCGGTCGCGGGTCCGGCTGCCCATCTCCTCCATCCG3461
CGCGCGCAGCCGCTCGCCCCAGGCCTGGGCCCGCTCCTGT
AGCGGCTGGCCGGCCAGGGAGCCCACAGTGGCGGCCCGCA
CCAGGCCTGGGGCGAGC3462
GCTCGCCCCAGGCCTGG3463
Apolipoprotein ECAGGCCTGGGGCGAGCGGCTGCGCGCGCGGATGGAGGAGA3464
Arg228CysTGGGCAGCCGGACCCGCGACCGCCTGGACGAGGTGAAGGA
cCGC-TGCGCAGGTGGCGGAGGTGCGCGCCAAGCTGGAGGAGCAGGCC
C
GGGCCTGCTCCTCCAGCTTGGCGCGCACCTCCGCCACCTGC3465
TCCTTCACCTCGTCCAGGCGGTCGCGGGTCCGGCTGCCCAT
CTCCTCCATCCGCGCGCGCAGCCGCTCGCCCCAGGCCTG
CCCGCGACCGCCTGGAC3466
GTCCAGGCGGTCGCGGG3467
Apolipoprotein ECGGACCCGCGACCGCCTGGACGAGGTGAAGGAGCAGGTGG3468
Glu244LysCGGAGGTGCGCGCCAAGCTGGAGGAGCAGGCCCAGCAGAT
gGAG-AAGACGCCTGCAGGCCGAGGCCTTCCAGGCCCGCCTCAAGAGCT
AGCTCTTGAGGCGGGCCTGGAAGGCCTCGGCCTGCAGGCGT3469
ATCTGCTGGGCCTGCTCCTCCAGCTTGGCGCGCACCTCCGC
CACCTGCTCCTTCACCTCGTCCAGGCGGTCGCGGGTCCG
CCAAGCTGGAGGAGCAG3470
CTGCTCCTCCAGCTTGG3471
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Familial Hypercholesterolemia—LDLR
[0147] Familial hypercholesterolemia is characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL) and is, hence, one of the conditions producing a hyperlipoproteinemia phenotype. Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene cause this disorder. The attached table discloses the correcting oligonucleotide base sequences for the LDLR oligonucleotides of the invention.
29TBALE 28
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LDLR Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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HypercholesterolaemiaGCGTTGAGAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGC3472
Glu10TermGACAGATGCGAAAGAAACGAGTTCCAGTGCCAAGACGGGAA
cGAG-TAGATGCATCTCCTACAAGTGGGTCTGCGATGGCAGCGCTG
CAGCGCTGCCATCGCAGACCCACTTGTAGGAGATGCATTTCC3473
CGTCTTGGCACTGGAACTCGTTTCTTTCGCATCTGTCGCCCA
CTGAGAGAGAGGAAAAGGAGAAAGGGTCTCTCAACGC
AAAGAAACGAGTTCCAG3474
CTGGAACTCGTTTCTTT3475
HypercholesterolaemiaAGAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGA3476
Gln12TermTGCGAAAGAAACGAGTTCCAGTGCCAAGACGGGAAATGCATC
cCAG-TAGTCCTACAAGTGGGTCTGCGATGGCAGCGCTGAGTGCC
GGCACTCAGCGCTGCCATCGCAGACCCACTTGTAGGAGATG3477
CATTTCCCGTCTTGGCACTGGAACTCGTTTCTTTCGCATCTGT
CGCCCACTGAGAGAGAGGAAAAGGAGAAAGGGTCTCT
ACGAGTTCCAGTGCCAA3478
TTGGCACTGGAACTCGT3479
HypercholesterolaemiaCCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGATGCGAA3480
Gln14TermAGAAACGAGTTCCAGTGCCAAGACGGGAAATGCATCTCCTAC
cCAA-TAAAAGTGGGTCTGCGATGGCAGCGCTGAGTGCCAGGATG
CATCCTGGCACTCAGCGCTGCCATCGCAGACCCACTTGTAG3481
GAGATGCATTTCCCGTCTTGGCACTGGAACTCGTTTCTTTCG
CATCTGTCGCCCACTGAGAGAGAGGAAAAGGAGAAAGG
TCCAGTGCCAAGACGGG3482
CCCGTCTTGGCACTGGA3483
HypercholesterolaemiaGCGACAGATGCGAAAGAAACGAGTTCCAGTGCCAAGACGGG3484
Trp23TermAAATGCATCTCCTACAAGTGGGTCTGCGATGGCAGCGCTGAG
TGG-TAGTGCCAGGATGGCTCTGATGAGTCCCAGGAGACGTGCTG
CAGCACGTCTCCTGGGACTCATCAGAGCCATCCTGGCACTCA3485
GCGCTGCCATCGCAGACCCACTTGTAGGAGATGCATTTCCCG
TCTTGGCACTGGAACTCGTTTCTTTCGCATCTGTCGC
CTACAAGTGGGTCTGCG3486
CGCAGACCCACTTGTAG3487
HypercholesterolaemiaAACGAGTTCCAGTGCCAAGACGGGAAATGCATCTCCTACAAG3488
Ala29SerTGGGTCTGCGATGGCAGCGCTGAGTGCCAGGATGGCTCTGA
cGCT-TCTTGAGTCCCAGGAGACGTGCTGTGAGTCCCCTTTGGGCA
TGCCCAAAGGGGACTCACAGCACGTCTCCTGGGACTCATCA3489
GAGCCATCCTGGCACTCAGCGCTGCCATCGCAGACCCACTT
GTAGGAGATGCATTTCCCGTCTTGGCACTGGAACTCGTT
ATGGCAGCGCTGAGTGC3490
GCACTCAGCGCTGCCAT3491
HypercholesterolaemiaTCCAGTGCCAAGACGGGAAATGCATCTCCTACAAGTGGGTCT3492
Cys31TyrGCGATGGCAGCGCTGAGTGCCAGGATGGCTCTGATGAGTCC
TGC-TACCAGGAGACGTGCTGTGAGTCCCCTTTGGGCATGATATG
CATATCATGCCCAAAGGGGACTCACAGCACGTCTCCTGGGAC3493
TCATCAGAGCCATCCTGGCACTCAGCGCTGCCATCGCAGAC
CCACTTGTAGGAGATGCATTTCCCGTCTTGGCACTGGA
CGCTGAGTGCCAGGATG3494
CATCCTGGCACTCAGCG3495
HypercholesterolaemiaAATCCTGTCTCTCTGTAGTGTCTGTCACCTGCAAATCCGGG3496
Arg57CysGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATTCCTCA
cCGT-TGTGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACAACG
CGTTGTCGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAG3497
GAATGCAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCG
GATTTGCAGGTGACAGACACTACAGAAGAGACAGGATT
GTGGGGGCCGTGTCAAC3498
GTTGACACGGCCCCCAC3499
HypercholesterolaemiaTCTGTCACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCG3500
Gln64TermTGTCAACCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCA
tCAG-TAGAGTGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTC
GACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCACTTGGC3501
CATCGCACCTCCAGAACTGAGGAATGCAGCGGTTGACACGG
CCCCCACAGCTGAAGTCCCCGGATTTGCAGGTGACAGA
GCATTCCTCAGTTCTGG3502
CCAGAACTGAGGAATGC3503
HypercholesterolaemiaACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAA3504
Trp66GlyCCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGG
cTGG-GGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGT
ACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCA3505
CTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCGGTTG
ACACGGCCCCCACAGCTGAAGTCCCCGGATTTGCAGGT
CTCAGTTCTGGAGGTGC3506
GCACCTCCAGAACTGAG3507
HypercholesterolaemiaCCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAAC3508
Trp66TermCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA
TGG-TAGCTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTG
CACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCC3509
ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCGGTTG
ACACGGCCCCCACAGCTGAAGTCCCCGGATTGCAGG
TCAGTTCTGGAGGTGCG3510
CGCACCTCCAGAACTGA3511
HypercholesterolaemiaAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTG3512
Cys68ArgCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGA
gTGC-CGCCAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCC
GGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGC3513
AGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAG
CGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATTT
TCTGGAGGTGCGATGGC3514
GCCATCGCACCTCCAGA3515
HypercholesterolaemiaATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCA3516
Cys68TrpTTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACA
TGCg-TGGACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCT
AGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC3517
GCAGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCA
GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGAT
TGGAGGTGCGATGGCCA3518
TGGCCATCGCACCTCCA3519
HypercholesterolaemiaAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGC3520
Cys68TyrATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGAC
TGC-TACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCC
GGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC3521
GCAGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCA
GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATT
CTGGAGGTGCGATGGCC3522
GGCCATCGCACCTCCAG3523
HypercholesterolaemiaTCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT3524
Asp69AsnTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACA
cGAT-AATACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTG
CAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT3525
CGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAATG
CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA
GGAGGTGCGATGGCCAA3526
TTGGCCATCGCACCTCC3527
HypercholesterolaemiaCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATT3528
Asp69GlyCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACAA
GAT-GGTCGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGC
GCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTT3529
GTCGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAAT
GCAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGG
GAGGTGCGATGGCCAAG3530
CTTGGCCATCGCACCTC3531
HypercholesterolaemiaTCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT3532
Asp69TyrTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACA
cGAT-TATACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTG
CAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT3533
CGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAGGAATG
CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA
GGAGGTGCGATGGCCAA3534
TTGGCCATCGCACCTCC3535
HypercholesterolaemiaGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATTCCTCA3536
Gln71GluGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACAACGGCT
cCAA-GAACAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCCTTTG
CAAAGGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAG3537
CCGTTGTCGCAGTCCACTTGGCCATCGCACCTCCAGAACTGA
GGAATGCAGCGGTTGACACGGCCCCCACAGCTGAAGTC
GCGATGGCCAAGTGGAC3538
GTCCACTTGGCCATCGC3539
HypercholesterolaemiaTGTGGGGGCCGTGTCAACCGCTGCATTCCTCAGTTCTGGAG3540
Cys74GlyGTGCGATGGCCAAGTGGACTGCGACAACGGCTCAGACGAGC
cTGC-GGCAAGGCTGTCGTAAGTGTGGCCCTGCCTTTGCTATTGAGC
GCTCAATAGCAAAGGCAGGGCCACACTTACGACAGCCTTGCT3541
CGTCTGAGCCGTTGTCGCAGTCCACTTGGCCATCGCACCTC
CAGAACTGAGGAATGCAGCGGTTGACACGGCCCCCACA
AAGTGGACTGCGACAAC3542
GTTGTCGCAGTCCACTT3543
HypercholesterolaemiaTCAACCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAG3544
Ser78TermTGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAG
TCA-TGATGTGGCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCT
AGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCACACTTA3545
CGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCACTTGG
CCATCGCACCTCCAGAACTGAGGAATGCAGCGGTTGA
CAACGGCTCAGACGAGC3546
GCTCGTCTGAGCCGTTG3547
HypercholesterolaemiaCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA3548
Glu80LysCTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTG
cGAG-AAGGCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGA
TCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA3549
CACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCC
ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG
GCTCAGACGAGCAAGGC3550
GCCTTGCTCGTCTGAGC3551
HypercholesterolaemiaCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA3552
Glu80TermCTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTG
cGAG-TAGGCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGA
TCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA3553
CACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCC
ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG
GCTCAGACGAGCAAGGC3554
GCCTTGCTCGTCTGAGC3555
HypercholesterolaemiaTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGC3556
Gln81TermGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCC
gCAA-TAATGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGAGTG
CACTCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGG3557
CCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAG
TCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCA
CAGACGAGCAAGGCTGT3558
ACAGCCTTGCTCGTCTG3559
HypercholesterolaemiaTGGGAGACTTCACACGGTGATGGTGGTCTCGGCCCATCCAT3560
Cys88ArgCCCTGCAGCCCCCAAGACGTGCTCCCAGGACGAGTTTCGCT
gTGC-CGCGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTCTGTG
CACAGACGAACTGCCGAGAGATGCACTTCCCATCGTGGCAG3561
CGAAACTCGTCCTGGGAGCACGTCTTGGGGGCTGCAGGGAT
GGATGGGCCGAGACCACCATCACCGTGTGAAGTCTCCCA
CCAAGACGTGCTCCCAG3562
CTGGGAGCACGTCTTGG3563
HypercholesterolaemiaCACGGTGATGGTGGTCTCGGCCCATCCATCCCTGCAGCCCC3564
Glu92TermCAAGACGTGCTCCCAGGACGAGTTTCGCTGCCACGATGGGA
cGAG-TAGAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGG
CCCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTTC3565
CCATCGTGGCAGCGAAACTCGTCCTGGGAGCACGTCTTGGG
GGCTGCAGGGATGGATGGGCCGAGACCACCATCACCGTG
CCCAGGACGAGTTTCGC3566
GCGAAACTCGTCCTGGG3567
HypercholesterolaemiaGGTGGTCTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTG3568
Cys95ArgCTCCCAGGACGAGTTTCGCTGCCACGATGGGAAGTGCATCT
cTGC-CGCCTCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGG
CCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGAGAG3569
ATGCACTTCCCATCGTGGCAGCGAAACTCGTCCTGGGAGCA
CGTCTTGGGGGCTGCAGGGATGGATGGGCCGAGACCACC
AGTTTCGCTGCCACGAT3570
ATCGTGGCAGCGAAACT3571
HypercholesterolaemiaCTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTGCTCCCA3572
Asp97TyrGGACGAGTTTCGCTGCCACGATGGGAAGTGCATCTCTCGGC
cGAT-TATAGTTCGTCTGTGACTCAGACCGGGACTGCTTGGACGGCT
AGCCGTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGC3573
CGAGAGATGCACTTCCCATCGTGGCAGCGAAACTCGTCCTG
GGAGCACGTCTTGGGGGCTGCAGGGATGGATGGGCCGAG
GCTGCCACGATGGGAAG3574
CTTCCCATCGTGGCAGC3575
HypercholesterolaemiaGGGTCGGGACACTGCCTGGCAGAGGCTGCGAGCATGGGGC3576
Trp(-12)ArgCCTGGGGCTGGAAATTGCGCTGGACCGTCGCCTTGCTCCTC
cTGG-AGGGCCGCGGCGGGGACTGCAGGTAAGGCTTGCTCCAGGCGCC
GGCGCCTGGAGCAAGCCTTACCTGCAGTCCCCGCCGCGGC3577
GAGGAGCAAGGCGACGGTCCAGCGCAATTTCCAGCCCCAGG
GCCCCATGCTCGCAGCCTCTGCCAGGCAGTGTCCCGACCC
AATTGCGCTGGACCGTC3578
GACGGTCCAGCGCAATT3579
HypercholesterolaemiaCAGCAGGTCGTGATCCGGGTCGGGACACTGCCTGGCAGAGG3580
Trp(-18)TermCTGCGAGCATGGGGCCCTGGGGCTGGAAATTGCGCTGGACC
TGGg-TGAGTCGCCTTGCTCCTCGCCGCGGCGGGGACTGCAGGTAAG
CTTACCTGCAGTCCCCGCCGCGGCGAGGAGCAAGGCGACG3581
GTCCAGCGCAATTTCCAGCCCCAGGGCCCCATGCTCGCAGC
CTCTGCCAGGCAGTGTCCCGACCCGGATCACGACCTGCTG
GGGCCCTGGGGCTGGAA3582
TTCCAGCCCCAGGGCCC3583
HypercholesterolaemiaCAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG3584
Met(-21)LeuCCTGGCAGAGGCTGCGAGCATGGGGCCCTGGGGCTGGAAA
cATG-TTGTTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGA
TCCCCGCCGCGGCGAGGAGCAAGGCGACGGTCCAGCGCAA3585
TTTCCAGCCCCAGGGCCCCATGCTCGCAGCCTCTGCCAGGC
AGTGTCCCGACCCGGATCACGACCTGCTGTGTCCTAGCTG
CTGCGAGCATGGGGCCC3586
GGGCCCCATGCTCGCAG3587
HypercholesterolaemiaCAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG3588
Met(-21)ValCCTGGCAGAGGCTGCGAGCATGGGGCCCTGGGGCTGGAAA
cATG-GTGTTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGA
TCCCCGCCGCGGCGAGGAGCAAGGCGACGGTCCAGCGCAA3589
TTTCCAGCCCCAGGGCCCCATGCTCGCAGCCTCTGCCAGGC
AGTGTCCCGACCCGGATCACGACCTGCTGTGTCCTAGCTG
CTGCGAGCATGGGGCCC3590
GGGCCCCATGCTCGCAG3591
HypercholesterolaemiaATCCCTGCAGCCCCCAAGACGTGCTCCCAGGACGAGTTTCG3592
Tle101PheCTGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTCTGTGA
cATC-TTCCTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCT
AGGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA3593
CAGACGAACTGCCGAGAGATGCACTTCCCATCGTGGCAGCG
AAACTCGTCCTGGGAGCACGTCTTGGGGGCTGCAGGGAT
GGAAGTGCATCTCTCGG3594
CCGAGAGATGCACTTCC3595
HypercholesterolaemiaGCCCCCAAGACGTGCTCCCAGGACGAGTTTCGCTGCCACGA3596
Gln104TermTGGGAAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCG
gCAG-TAGGGACTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGG
CCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCAGTCCCG3597
GTCTGAGTCACAGACGAACTGCCGAGAGATGCACTTCCCATC
GTGGCAGCGAAACTCGTCCTGGGAGCACGTCTTGGGGGC
TCTCTCGGCAGTTCGTC3598
GACGAACTGCCGAGAGA3599
HypercholesterolaemiaTTTCGCTGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTC3600
Cys113ArgTGTGACTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGC
cTGC-CGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTCC
GGAAGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGC3601
CTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCACAGA
CGAACTGCCGAGAGATGCACTTCCCATCGTGGCAGCGAAA
ACCGGGACTGCTTGGAC3602
GTCCAAGCAGTCCCGGT3603
HypercholesterolaemiaAAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC3604
Glu119LysTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCAC
cGAG-AAGCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCT
AGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG3605
AGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCAGTC
CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT
GCTCAGACGAGGCCTCC3606
GGAGGCCTCGTCTGAGC3607
HypercholesterolaemiaAAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC3608
Glu119TermTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCAC
cGAG-TAGCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCT
AGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG3609
AGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCAGTC
CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT
GCTCAGACGAGGCCTCC3610
GGAGGCCTCGTCTGAGC3611
HypercholesterolaemiaTCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGGACG3612
Cys122TermGCTCAGACGAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCC
TGCc-TGAGCCAGCTTCCAGTGCAACAGCTCCACCTGCATCCCCCAG
CTGGGGGATGCAGGTGGAGCTGTTGCACTGGAAGCTGGCGG3613
GACCACAGGTGAGCACCGGGCAGGAGGCCTCGTCTGAGCC
GTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGA
GCCTCCTGCCCGGTGCT3614
AGCACCGGGCAGGAGGC3615
HypercholesterolaemiaTGACTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCT3616
Cys127TrpCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTCCAGTGC
TGTg-TGGAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGAC
GTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGC3617
ACTGGAAGCTGGCGGGACCACAGGTGAGCACCGGGCAGGA
GGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA
CTCACCTGTGGTCCCGC3618
GCGGGACCACAGGTGAG3619
HypercholesterolaemiaTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCAC3620
Gln133TermCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCAT
cCAG-TAGCCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCG
CGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT3621
GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGG
TGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCA
CCAGCTTCCAGTGCAAC3622
GTTGCACTGGAAGCTGG3623
HypercholesterolaemiaTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCACCTG3624
Cys134GlyTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATCC
gTGC-GGCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAG
CTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGG3625
ATGCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA
GGTGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAA
GCTTCCAGTGCAACAGC3626
GCTGTTGCACTGGAAGC3627
HypercholesterolaemiaGAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTT3628
Cys139GlyCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCT
cTGC-GGCGCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGT
ACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAG3629
GCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA
GCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCTC
GCTCCACCTGCATCCCC3630
GGGGATGCAGGTGGAGC3631
HypercholesterolaemiaAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTC3632
Cys139TyrCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTG
TGC-TACCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGTG
CACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCA3633
GGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGA
AGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCT
CTCCACCTGCATCCCCC3634
GGGGGATGCAGGTGGAG3635
HypercholesterolaemiaCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCAT3636
Cys146TermCCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAG
TGCg-TGAATGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTT
AAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTTC3637
GCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGATG
CAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAG
TGGGCCTGCGACAACGA3638
TCGTTGTCGCAGGCCCA3639
HypercholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC3640
Asp147AsnCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAGA
cGAC-AACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT
AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT3641
CGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT
GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA
GGGCCTGCGACAACGAC3642
GTCGTTGTCGCAGGCCC3643
HypercholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC3644
Asp147HisCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAGA
cGAC-CACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT
AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCT3645
CGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT
GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA
GGGCCTGCGACAACGAC3646
GTCGTTGTCGCAGGCCC3647
HypercholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC3648
Asp147TyrCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAGA
cGAC-TACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT
AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT3649
CGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT
GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA
GGGCCTGCGACAACGAC3650
GTCGTTGTCGCAGGCCC3651
HypercholesterolaemiaTTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGC3652
Cys152ArgCTGCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGT
cTGC-CGCGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGG
CCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC3653
TCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAGGC
CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA
ACCCCGACTGCGAAGAT3654
ATCTTCGCAGTCGGGGT3655
HypercholesterolaemiaTTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGC3656
Cys152GlyCTGCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGT
cTGC-GGCGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGG
CCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC3657
TCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAGGC
CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA
ACCCCGACTGCGAAGAT3658
ATCTTCGCAGTCGGGGT3659
HypercholesterolaemiaCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCT3660
Cys152TrpGCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGTGG
TGCg-TGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGAC
GTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCC3661
ACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAG
GCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGG
CCCGACTGCGAAGATGG3662
CCATCTTCGCAGTCGGG3663
HypercholesterolaemiaTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGA3664
Asp154AsnCAACGACCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGC
aGAT-AATAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGACAGTA
TACTGTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCG3665
GCCACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTGTCG
CAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCA
ACTGCGAAGATGGCTCG3666
CGAGCCATCTTCGCAGT3667
HypercholesterolaemiaGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGACAACGAC3668
Ser156LeuCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGCAGCGCTG
TCG-TTGTAGGGGTCTTTACGTGTTCCAAGGGGACAGTAGCCCCTG
CAGGGGCTACTGTCCCCTTGGAACACGTAAAGACCCCTACAG3669
CGCTGCGGCCACTCATCCGAGCCATCTTCGCAGTCGGGGTC
GTTGTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGC
AGATGGCTCGGATGAGT3670
ACTCATCCGAGCCATCT3671
HypercholesterolaemiaTGTGGGCCTGCGACAACGACCCCGACTGCGAAGATGGCTCG3672
Cys163TyrGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAA
TGT-TATGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG
CAGTGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG3673
GAACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG
AGCCATCTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACA
GCAGCGCTGTAGGGGTC3674
GACCCCTACAGCGCTGC3675
HypercholesterolaemiaCAACGACCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGC3676
Tyr167TermAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGACAGTAGC
TACg-TAGCCCTGCTCGGCCTTCGAGTTCCACTGCCTAAGTGGCGAG
CTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAGCAGGGGC3677
TACTGTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCG
GCCACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTG
GGTCTTTACGTGTTCCA3678
TGGAACACGTAAAGACC3679
HypercholesterolaemiaCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGCAGCGCTG3680
Gln170TermTAGGGGTCTTTACGTGTTCCAAGGGGACAGTAGCCCCTGCTC
cCAA-TAAGGCCTTCGAGTTCCACTGCCTAAGTGGCGAGTGCATCC
GGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAG3681
CAGGGGCTACTGTCCCCTTGGAACACGTAAAGACCCCTACAG
CGCTGCGGCCACTCATCCGAGCCATCTTCGCAGTCGGG
ACGTGTTCCAAGGGGAC3682
GTCCCCTTGGAACACGT3683
HypercholesterolaemiaCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC3684
Cys176PheCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG
TGC-TTCCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA
TCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA3685
GTGGAACTCGAAGGCCCGAGCAGGGGCTACTGTCCCCTTGGA
ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG
TAGCCCCTGCTCGGCCT3686
AGGCCGAGCAGGGGCTA3687
HypercholesterolaemiaCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC3688
Cys176TyrCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG
TGC-TACCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA
TCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA3689
GTGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTGGA
ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG
TAGCCCCTGCTCGGCCT690
AGGCCGAGCAGGGGCTA3691
HypercholesterolaemiaATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAG3692
Ser177LeuGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTGCCTA
TCG-TTGAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGG
CCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAG3693
GCAGTGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTT
GGAACACGTAAAGACCCCTACAGCGCTGCGGCCACTCAT
CCCCTGCTCGGCCTTCG3694
CGAAGGCCGAGCAGGGG3695
HypercholesterolaemiaTACGTGTTCCAAGGGGACAGTAGCCCCTGCTCGGCCTCGA3696
Glu187LysGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGC
cGAG-AAGGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACG
CGTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGC3697
CAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC
GAAGGCCGAGCAGGGGCTACTGTCCCCTTGGAACACGTA
TAAGTGGCGAGTGCATC3698
GATGCACTCGCCACTTA3699
HypercholesterolaemiaCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG3700
His190TyrCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATG
cCAC-TACGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACT
AGTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCAT3701
CACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCAG
TGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG
AGTGCATCCACTCCAGC3702
GCTGGAGTGGATGCACT3703
HypercholesterolaemiaCCTTCGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCA3704
Gly198AspGCTGGCGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCT
GGC-GACGACGAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGG
CCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCGTCAGAT3705
TTGTCCTTGCAGTCGGGGCCACCATCACAGCGCCAGCTGGA
GTGGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGG
TGATGGTGGCCCCGACT3706
AGTCGGGGCCACCATCA3707
HypercholesterolaemiaGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTG3708
Asp200AsnGCGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACG
cGAC-AACTAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGG
CCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCG3709
TCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGCCAG
CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC
GTGGCCCCGACTGCAAG3710
CTTGCAGTCGGGGCCAC3711
HypercholesterolaemiaAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGC3712
Asp200GlyGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACGAG
GAC-GGCGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGG
CCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTC3713
GTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGCCA
GCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACT
TGGCCCCGACTGCAAGG3714
CCTTGCAGTCGGGGCCA3715
HypercholesterolaemiaGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTG3716
Asp200TyrGCGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACG
cGAC-TACAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGG
CCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCG3717
TCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGCCAG
CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC
GTGGCCCCGACTGCAAG3718
CTTGCAGTCGGGGCCAC3719
HypercholesterolaemiaCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCT3720
Cys201TermGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAA
TGCa-TGAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGT
ACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTT3721
CCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGC
GCCAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGG
CCCGACTGCAAGGACAA3722
TTGTCCTTGCAGTCGGG3723
HypercholesterolaemiaTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGC3724
Cys201TyrTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACGAGGA
TGC-TACAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCG
CGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTC3725
CTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCG
CCAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGA
CCCCGACTGCAAGGACA3726
TGTCCTTGCAGTCGGGG3727
HypercholesterolaemiaTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA3728
Asp203AsnTGGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACT
gGAC-AACGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTA
TAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA3729
GTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATC
ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA
ACTGCAAGGACAAATCT3730
AGATTTGTCCTGCAGT3731
HypercholesterolaemiaGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT3732
Asp203GlyGGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACTG
GAC-GGCCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTAT
ATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA3733
GTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATC
ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC
CTGCAAGGACAAATCTG 3734
CAGATTTGTCCTTGCAG 3735
HypercholesterolaemiaGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT3736
Asp203ValGGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACTG
GAC-GTCCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTAT
ATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA3737
GTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATC
ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC
CTGCAAGGACAAATCTG3738
CAGATTTGTCCTTGCAG3739
HypercholesterolaemiaAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGG3740
Ser205ProCCCCGACTGCAAGGACAAATCTGACGAGGAAAACTGCGGTAT
aTCT-CCTGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCT
AGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATA3741
CCGCAGTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCA
CCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACT
AGGACAAATCTGACGAG3742
CTCGTCAGATTTGTCCT3743
HypercholesterolaemiaCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCG3744
Asp206GluACTGCAAGGACAAATCTGACGAGGAAAACTGCGGTATGGGC
GACg-GAGGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCC
GGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCG3745
CCCATACCGCAGTTTTCCTCGTCAGATTTGTCCTTGCAGTCG
GGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTCG
AAATCTGACGAGGAAAA3746
TTTTCCTCGTCAGATTT3747
HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA3748
Glu207GlnCTGCAAGGACAAATCTGACGAGGAAAACTGCGGTATGGGCG
cGAG-CAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT
AGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC3749
GCCCATACCGCAGTTTTCCTCGTCAGATTTGTCCTTGCAGTC
GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC
AATCTGACGAGGAAAAC3760
GTTTTCCTCGTCAGATT3751
HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA3752
Glu207LysCTGCAAGGACAAATCTGACGAGGAAAACTGCGGTATGGGCG
cGAG-AAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT
AGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC3753
GCCCATACCGCAGTTTTCCTCGTCAGATTTGTCCTTGCAGTC
GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC
AATCTGACGAGGAAAAC3754
GTTTTCCTCGTCAGATT3755
HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA3756
Glu207TermCTGCAAGGACAAATCTGACGAGGAAAACTGCGGTATGGGCG
cGAG-TAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT
AGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC3757
GCCCATACCGCAGTTTTCCTCGTCAGATTTGTCCTTGCAGTC
GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC
AATCTGACGAGGAAAAC3758
GTTTTCCTCGTCAGATT3759
HypercholesterolaemiaTCTTGAGAAAATCAACACACTCTGTCCTGTTTTCCAGCTGTGG3760
Glu219LysCCACCTGTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACT
cGAA-AAAGCATCCATGGCAGCCGGCAGTGTGACCGGGAATATG
CATATTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTTC3761
CATCAGAGCACTGGAATTCGTCAGGGCGACAGGTGGCCACA
GCTGGAAAACAGGACAGAGTGTGTTGATTTTCTCAAGA
GCCCTGACGAATTCCAG3762
CTGGAATTCGTCAGGGC3763
HypercholesterolaemiaGAAAATCAACACACTCTGTCCTGTTTTCCAGCTGTGGCCACCT3764
Gln221TermGTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCC
cCAG-TAGATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCA
TGCAGTCATATTCCCGGTCACACTGCCGGCTGCCATGGATGC3765
AGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGACAGGTGG
CCACAGCTGGAAAACAGGACAGAGTGTGTTGATTTTC
ACGAATTCCAGTGCTCT3766
AGAGCACTGGAATTCGT3767
HypercholesterolaemiaCCTGTTTTCCAGCTGTGGCCACCTGTCGCCCTGACGAATTCC3768
Cys227PheAGTGCTCTGATGGAAACTGCATCCATGGCAGCCGGCAGTGT
TGC-TTCGACCGGGAATATGACTGCAAGGACATGAGCGATGAAGT
ACTTCATCGCTCATGTCCTTGCAGTCATATTCCCGGTCACACT3769
GCCGGCTGCCATGGATGCAGTTTCCATCAGAGCACTGGAATT
CGTCAGGGCGACAGGTGGCCACAGCTGGAAAACAGG
TGGAAACTGCATCCATG3770
CATGGATGCAGTTTCCA3771
HypercholesterolaemiaTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCA3772
Asp235GluTGGCAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGACA
GACc-GAATGAGCGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGG
CCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTC3773
CTTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCATGGAT
GCAGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGA
CAGTGTGACCGGGAATA3774
TATTCCCGGTCACACTG3775
HypercholesterolaemiaGTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCC3776
Asp235GlyATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGAC
GAC-GGCATGAGCGATGAAGTTGGCTGCGTTAATGGTGAGCGCTG
CAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTCC3777
TTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCATGGATG
CAGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGAC
GCAGTGTGACCGGGAAT3778
ATTCCCGGTCACACTGC3779
HypercholesterolaemiaCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCATGGC3780
Glu237LysAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGACATGAG
gGAA-AAACGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGGCCAT
ATGGCCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCA3781
TGTCCTTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCAT
GGATGCAGTTTCCATCAGAGCACTGGAATTCGTCAGG
GTGACCGGGAATATGAC3782
GTCATATTCCCGGTCAC3783
HypercholesterolaemiaTCCAGTGCTCTGATGGAAACTGCATCCATGGCAGCCGGCAGT3784
Cys240PheGTGACCGGGAATATGACTGCAAGGACATGAGCGATGAAGTTG
TGC-TTCGCTGCGTTAATGGTGAGCGCTGGCCATCTGGTTTTCC
GGAAAACCAGATGGCCAGCGCTCACCATTAACGCAGCCAACT3785
TCATCGCTCATGTCCTTGCAGTCATATTCCCGGTCACACTGC
CGGCTGCCATGGATGCAGTTTCCATCAGAGCACTGGA
ATATGACTGCAAGGACA3786
TGTCCTTGCAGTCATAT3787
HypercholesterolaemiaAAACTGCATCCATGGCAGCCGGCAGTGTGACCGGGAATATG3788
Asp245GluACTGCAAGGACATGAGCGATGAAGTTGGCTGCGTTAATGGTG
GATg-GAAAGCGCTGGCCATCTGGTTTTCCATCCCCCATTCTCTGT
ACAGAGAATGGGGGATGGAAAACCAGATGGCCAGCGCTCAC3789
CATTAACGCAGCCAACTTCATCGCTCATGTCCTTGCAGTCATA
TTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTT
ATGAGCGATGAAGTTGG3790
CCAACTTCATCGCTCAT3791
HypercholesterolaemiaATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGAC3792
Cys249TyrATGAGCGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGGCC
TGC-TACATCTGGTTTTCCATCCCCCATCTCTGTGCCTTGCTGCT
AGCAGCAAGGCACAGAGAATGGGGGATGGAAAACCAGATGG3793
CCAGCGCTCACCATTAACCCAGCCAACTTCATCGCTCATGTC
CTTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCAT
AGTTGGCTGCGTTAATG3794
CATTAACGCAGCCAACT3795
HypercholesterolaemiaAGGCTCAGACACACCTGACCTTCCTCCTTCCTCTCTCTGGCT3796
Glu256LysCTCACAGTGACACTCTGCGAGGGACCCAACAAGTTCAAGTGT
cGAG-AAGCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCA
TGCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACACT3797
TGAACTTGTTGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCA
GAGAGAGGAAGGAGGAAGGTCAGGTGTGTCTGAGCCT
CACTCTGCGAGGGACCC3798
GGGTCCCTCGCAGAGTG3799
HypercholesterolaemiaCCTCTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAA3800
Ser265ArgCAAGTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAA
AGCg-AGAAGTCTGCAACATGGCTAGAGACTGCCGGGACTGGTCA
TGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTTTGTC380T
CAGGGTGATGCATTCGCCGCTGTGACACTTGAACTTGTTGGG
TCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGAGAGG
TGTCACAGCGGCGAATG3802
CATTCGCCGCTGTGACA3803
HypercholesterolaemiaTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAACAAG3804
Glu267LysTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTC
cGAA-AAATGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATG
CATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTT3805
TGTCCAGGGTGATGCATTCGCCGCTGTGACACTTGAACTTGT
TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA
ACAGCGGCGAATGCATC3806
GATGCATTCGCCGCTGT3807
HypercholesterolaemiaTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAACAAG3808
Glu267TermTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTC
cGAA-TAATGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATG
CATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTT3809
TGTCCAGGGTGATGCATTCGCCGCTGTGACACTTGAACTTGT
TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA
ACAGCGGCGAATGCATC3810
GATGCATTCGCCGCTGT3811
HypercholesterolaemiaACACTCTGCGAGGGACCCAACAAGTTCAAGTGTCACAGCGG3812
Lys273GluCGAATGCATCACCCTGGACAAAGTCTGCAACATGGCTAGAGA
cAAA-GAACTGCCGGGACTGGTCAGATGAACCCATCAAAGAGTGCG
CGCACTCTTTGATGGGTTCATCTGACCAGTCCCGGCAGTCTC3813
TAGCCATGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGC
TGTGACACTTGAACTTGTTGGGTCCCTCGCAGAGTGT
CCCTGGACAAAGTCTGC3814
GCAGACTTTGTCCAGGG3815
HypercholesterolaemiaCGAGGGACCCAACAAGTTCAAGTGTCACAGCGGCGAATGCA3816
Cys275TermTCACCCTGGACAAAGTCTGCAACATGGCTAGAGACTGCCGG
TGCa-TGAGACTGGTCAGATGAACCCATCAAAGAGTGCGGTGAGTCT
AGACTCACCGCACTCTTTGATGGGTTCATCTGACCAGTCCCG3817
GCAGTCTCTAGCCATGTTGCAGACTTTGTCCAGGGTGATGCA
TTCGCCGCTGTGACACTTGAACTTGTTGGGTCCCTCG
AAAGTCTGCAACATGGC3818
GCCATGTTGCAGACTTT3819
HypercholesterolaemiaAGTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAG3820
Asp280GlyTCTGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATGAA
GAC-GGCCCCATCAAAGAGTGCGGTGAGTCTCGGTGCAGGCGGCT
AGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGGTTCA3821
TCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTTTG
TCCAGGGTGATGCATTCGCCGCTGTGACACTTGAACT
GGCTAGAGACTGCCGGG3822
CCCGGCAGTCTCTAGCC3823
HypercholesterolaemiaTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCT3824
Cys281TyrGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATGAACCC
TGC-TACATCAAAGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGC
GCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGG3825
TTCATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGAC
TTTGTCCAGGGTGATGCATTCGCCGCTGTGACACTTGA
TAGAGACTGCCGGGACT3826
AGTCCCGGCAGTCTCTA3827
HypercholesterolaemiaTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC3828
Asp283AsnATGGCTAGAGACTGCCGGGACTGGTCAGATGAACCCATCAAA
gGAC-AACGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGT
ACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA3829
TGGGTTCATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGC
AGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACA
ACTGCCGGGACTGGTCA3830
TGACCAGTCCCGGCAGT3831
HypercholesterolaemiaTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACAT3832
Asp283GluGGCTAGAGACTGCCGGGACTGGTCAGATGAACCCATCAAAG
GACt-GAGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTT
AAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTT3833
GATGGGTTCATCTGACCAGTCCCGGCAGTCTCTAGCCATGTT
GCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGA
TGCCGGGACTGGTCAGA3834
TCTGACCAGTCCCGGCA3835
HypercholesterolaemiaGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC3836
Asp283TyrATGGCTAGAGACTGCCGGGACTGGTCAGATGAACCCATCAAA
gGAC-TACGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGT
ACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA3837
TGGGT~CATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGC
AGACTTGTCCAGGGTGATGCATTCGCCGCTGTGACA
ACTGCCGGGACTGGTCA3838
TGACCAGTCCCGGCAGT3839
HypercholesterolaemiaCAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGG3840
Trp284TermCTAGAGACTGCCGGGACTGGTCAGATGAACCCATCAAAGAGT
TGGt-TGAGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTG
CACAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACT3841
CTTTGATGGGTTCATCTGACCAGTCCCGGCAGTCTCTAGCCA
TGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGCTG
CGGGACTGGTCAGATGA3842
TCATCTGACCAGTCCCG3843
HypercholesterolaemiaGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGGCTA3844
Ser285LeuGAGACTGCCGGGACTGGTCAGATGAACCCATCAAAGAGTGC
TCA-TTAGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTGGG
CCCACAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCA3845
CTCTTTGATGGGTTCATCTGACCAGTCCCGGCAGTCTCTAGC
CATGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGC
GGACTGGTCAGATGAAC3846
GTTCATCTGACCAGTCC3847
HypercholesterolaemiaCCCTGGACAAAGTCTGCAACATGGCTAGAGACTGCCGGGAC3848
Lys290ArgTGGTCAGATGAACCCATCAAAGAGTGCGGTGAGTCTCGGTG
AAA-AGACAGGCGGCTTGCAGAGTTTGTGGGGAGCCAGGAAAGGGA
TCCCTTTCCTGGCTCCCCACAAACTCTGCAAGCCGCCTGCAC3849
CGAGACTCACCGCACTCTTTGATGGGTTCATCTGACCAGTCC
CGGCAGTCTCTAGCCATGTTGCAGACTTTGTCCAGGG
ACCCATCAAAGAGTGCG3850
CGCACTCTTTGATGGGT3851
HypercholesterolaemiaGGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC3852
Cys297PheTGCGCAGGGACCAACGAATGCTTGGACAACAACGGCGGCTG
TGC-TTCTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTG
CACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG3853
CCGCCGTTGTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGG
CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC
CAACGAATGCTTGGACA3854
TGTCCAAGCATTCGTTG3855
HypercholesterolaemiaGGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC3856
Cys297TyrTGCGCAGGGACCAACGAATGCTTGGACAACAACGGCGGCTG
TGC-TACTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTG
CACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG3857
CCGCCGTTGTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGG
CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC
CAACGAATGCTTGGACA3858
TGTCCAAGCATTCGTTG3859
HypercholesterolaemiaTGCATCCCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGA3860
His306TyrCAACAACGGCGGCTGTTCCCACGTCTGCAATGACCHAAGAT
cCAC-TACCGGCTACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGG
CCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAGCCGATC3861
TTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCC
AAGCATTCGTTGGTCCCTGCGCAGGGCCAGGGGATGCA
GCTGTTCCCACGTCTGC3862
GCAGACGTGGGAACAGC3863
HypercholesterolaemiaCCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAA3864
Cys308GlyCGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTA
cTGC-GGCCGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCC
GGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA3865
GCCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGT
TGTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGGG
CCCACGTCTGCAATGAC3866
GTCATTGCAGACGTGGG3867
HypercholesterolaemiaCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAAC3868
Cys308TyrGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTAC
TGC-TACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCA
TGGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA3869
GCCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTT
GTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGG
CCACGTCTGCAATGACC3870
GGTCATTGCAGACGTGG3871
HypercholesterolaemiaACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTC3872
Gly3l4SerTGCAATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGAC
cGGC-AGCGGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTG
CACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTCG3873
GGGCACAGGCACTCGTAGCCGATCTTAAGGTCATTGCAGAC
GTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGGT
TTAAGATCGGCTACGAG3874
CTCGTAGCCGATCTTAA3875
HypercholesterolaemiaCCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCT3876
Gly314ValGCAATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGAC
GGC-GTCGGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGA
TCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTC3877
GGGGCACAGGCACTCGTAGCCGATCTTAAGGTCATTGCAGA
CGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGG
TAAGATCGGCTACGAGT3878
ACTCGTAGCCGATCTTA3879
HypercholesterolaemiaCGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAA3880
Tyr315TermTGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGCTT
TACg-TAACCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTC
GAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCC3881
CTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCATTGCA
GACGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCG
ATCGGCTACGAGTGCCT3882
AGGCACTCGTAGCCGAT3883
HypercholesterolaemiaTGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAATGAC3884
Cys317GlyCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGCTTCCA
gTGC-GGCGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGG
CCCGGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGG3885
AAGCCGTCGGGGCACAGGCACTCGTAGCCGATCTAAGGTC
ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA
GCTACGAGTGCCTGTGC3886
GCACAGGCACTCGTAGC3887
HypercholesterolaemiaTGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAATGAC3888
Cys317SerCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGCTTCCA
gTGC-AGCGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGG
CCCGGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGG3889
AAGCCGTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTC
ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA
GCTACGAGTGCCTGTGC3890
GCACAGGCACTCGTAGC3891
HypercholesterolaemiaACAACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCG3892
Pro320ArgGCTACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCC
CCC-CGCCAGCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAG
CTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGGCC3893
ACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAGCCGAT
CTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTTGT
CCTGTGCCCCGACGGCT3894
AGCCGTCGGGGCACAGG3895
HypercholesterolaemiaAACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGC3896
Asp321AsnTACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCA
cGAC-AACGCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCC
GGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGG3897
CCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAGCCG
ATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTT
TGTGCCCCGACGGCTTC3898
GAAGCCGTCGGGGCACA3899
HypercholesterolaemiaCGGCGGCTGTTCCCACGTCTGCAATGACCT~AAGATCGGCTA3900
Asp321GluCGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCAGC
GACg-GAGGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCCT
AGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTG3901
GGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAG
CCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCG
TGCCCCGACGGCTTCCA3902
TGGAAGCCGTCGGGGCA3903
HypercholesterolaemiaGGCGGCTGTTCCCACGTGTGCAATGACCTTAAGATCGGCTAC3904
Gly322SerGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCAGCG
cGGC-AGCAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCCTG
CAGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCT3905
GGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA
GCCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCC
GCCCCGACGGCTTCCAG3906
CTGGAAGCCGTCGGGGC3907
HypercholesterolaemiaTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTGC3908
Gln324TermCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCAGCGAAGATG
cCAG-TAGCGAAGGTGATTTCCGGGTGGGACTGAGCCCTGGGCCCC
GGGGCCCAGGGCTCAGTCCCACCCGGAAATCACCTTCGCAT3909
CTTCGCTGGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCA
CTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACA
ACGGCTTCCAGCTGGTG3910
CACCAGCTGGAAGCCGT3911
HypercholesterolaemiaATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGC3912
Arg329ProTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCG
CGA-CCAGGTGGGACTGAGCCCTGGGCCCCCTCTGCGCTTCCTGAC
GTCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCC3913
GGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAG
CCGTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCAT
GGCCCAGCGAAGATGCG3914
CGCATCTTCGCTGGGCC3915
HypercholesterolaemiaAATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGG3916
Arg329TermCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCC
gCGA-TGAGGGTGGGACTGAGCCCTGGGCCCCCTCTGCGCTTCCTGA
TCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCCG3917
GAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCC
GTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCATT
TGGCCCAGCGAAGATGC3918
GCATCTTCGCTGGGCCA3919
HypercholesterolaemiaTCTAGCCATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTC3920
Glu336LysTCTCTTCCAGATATCGATGAGTGTCAGGATCCCGACACCTGC
tGAG-AAGAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGT
ACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCAG3921
GTGTCGGGATCCTGACACTCATCGATATCTGGAAGAGAGAGA
AAGAGGCTTGGTGGGGAGGCTCTTCCCCAATGGCTAGA
ATATCGATGAGTGTCAG3922
CTGACACTCATCGATAT3923
HypercholesterolaemiaCATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTCTCTCTT3924
Gln338TermCCAGATATCGATGAGTGTCAGGATCCCGACACCTGCAGCCAG
tCAG-TAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTGCCAGT
ACTGGCATTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGG3925
CTGCAGGTGTCGGGATCCTGACACTCATCGATATCTGGAAGA
GAGAGAAAGAGGCTTGGTGGGGAGGCTCTTCCCCAATG
ATGAGTGTCAGGATCCC3926
GGGATCCTGACACTCAT3927
HypercholesterolaemiaTCCCCACCAAGCCTCTTTCTCTCTCTTCCAGATATCGATGAGT3928
Cys343ArgGTCAGGATCCCGACACCTGCAGCCAGCTCTGCGTGAACCTG
cTGC-CGCGAGGGTGGCTACAAGTGCCAGTGTGAGGAAGGCTTCC
GGAAGCCTTCCTCACACTGGCACTTGTAGCCACCCTCCAGGT3929
TCACGCAGAGCTGGCTGCAGGTGTCGGGATCCTGACACTCA
TCGATATCTGGAAGAGAGAGAAAGAGGCTTGGTGGGGA
CCGACACCTGCAGCCAG3930
CTGGCTGCAGGTGTCGG3931
HypercholesterolaemiaCAAGCCTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGA3932
Gln345ArgTCCCGACACCTGCAGCCAGCTCTGCGTGAACCTGGAGGGTG
CAG-CGGGCTACAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGA
TCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTAGCCACCC3933
TCCAGGTTCACGCAGAGCTGGCTGCAGGTGTCGGGATCCTG
ACACTCATCGATATCTGGAAGAGAGAGAAAGAGGCTTG
CTGCAGCCAGCTCTGCG3934
CGCAGAGCTGGCTGCAG3935
HypercholesterolaemiaTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCGA3936
Cys347TyrCACCTGCAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACA
TGC-TACAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCCA
TGGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTA3937
GCCACCCTCCAGGTTCACGCAGAGCTGGCTGCAGGTGTCGG
GATCCTGACACTCATCGATATCTGGAAGAGAGAGAAAGA
CCAGCTCTGCGTGAACC3938
GGTTCACGCAGAGCTGG3939
HypercholesterolaemiaCTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCG3940
Cys347ArgACACCTGCAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTAC
cTGC-CGCAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCC
GGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTAG3941
CCACCCTCCAGGTTCACGCAGAGCTGGCTGCAGGTGTCGGG
ATCCTGACACTCATCGATATCTGGAAGAGAGAGAAAGAG
GCCAGCTCTGCGTGAAC3942
GTTCACGCAGAGCTGGC3943
HypercholesterolaemiaCAGATATCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGC3944
Gly352AspTCTGCGTGAACCTGGAGGGTGGCTACAAGTGCCAGTGTGAG
GGT-GATGAAGGCTTCCAGCTGGACCCCCACACGAAGGCCTGCAA
TTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCCTTCCTC3945
ACACTGGCACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTG
GCTGCAGGTGTCGGGATCCTGACACTCATCGATATCTG
CCTGGAGGGTGGCTACA3946
TGTAGCCACCCTCCAGG3947
HypercholesterolaemiaTCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGCTCTGC3948
Tyr354CysGTGAACCTGGAGGGTGGCTACAAGTGCCAGTGTGAGGAAGG
TAC-TGCCTTCCAGCTGGACCCCCACACGAAGGCCTGCAAGGCTGT
ACAGCCTTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCC3949
TTCCTCACACTGGCACTTGTAGCCACCCTCCAGGTTCACGCA
GAGCTGGCTGCAGGTGTCGGGATCCTGACACTCATCGA
GGGTGGCTACAAGTGCC3950
GGCACTTGTAGCCACCC3951
HypercholesterolaemiaCAGGATCCCGACACCTGCAGCCAGCTCTGCGTGAACCTGGA3952
Cys358ArgGGGTGGCTACAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGG
gTGT-CGTACCCCCACACGAAGGCCTGCAAGGCTGTGGGTGAGCACG
CGTGCTCACCCACAGCCTTGCAGGCCTTCGTGTGGGGGTCC3953
AGCTGGAAGCCTTCCTCACACTGGCACTTGTAGCCACCCTCC
AGGTTCACGCAGAGCTGGCTGCAGGTGTCGGGATCCTG
AGTGCCAGTGTGAGGAA3954
TTCCTCACACTGGCACT3955
HypercholesterolaemiaTGCAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTG3956
Gln363TermCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCCACACGAAGG
cCAG-TAGCCTGCAAGGCTGTGGGTGAGCACGGGAAGGCGGCGGGTG
CACCCGCCGCCTTCCCGTGCTCACCCACAGCCTTGCAGGCC3957
TTCGTGTGGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCA
CTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCA
AAGGCTTCCAGCTGGAC3958
GTCCAGCTGGAAGCCTT3959
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UDP-glucuronosyltransferase—UGT1
[0148] Mutations in the human UGT1 gene result in a range of disease syndromes, ranging from relatively common diseases such as Gilbert's syndrome, which effects up to 7% of the population, to rare disorders such as Crigler-Najjar syndrome. Symptoms of these diseases are the result of diminished bilirubin conjugation and typically present with jaundice or, when mild, as an incidental finding during routing laboratory analysis. Severe cases of Crigler-Najjar syndrome are caused by an absence of UGT1 activity and the majority of these patients die in the neonatal period. The only known treatment is liver transplant. The attached table discloses the correcting oligonucleotide base sequences for the UGT1 oligonucleotides of the invention.
30TABLE 29
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UGT1 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
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Crigler-Najjar syndromeGCAGGAGCAAAGGCGCCATGGCTGTGGAGTCCCAGGGCGG3960
2ACGCCCACTTGTCCTGGGCCTGCTGCTGTGTGTGCTGGGCC
Leu15ArgCAGTGGTGTCCCATGCTGGGAAGATACTGTTGATCCCAGT
CTG-CGGACTGGGATCAACAGTATCTTCCCAGCATGGGACACCACTGGG3961
CCCAGCACACACAGCAGCAGGCCCAGGACAAGTGGGCGTCC
GCCCTGGGACTCCACAGCCATGGCGCCTTTGCTCCTGC
CCTGGGCCTGCTGCTGT3962
ACAGCAGCAGGCCCAGG3963
Crigler-Najjar syndromeGGGAAGATACTGTTGATCCCAGTGGATGGCAGCCACTGGCT3964
1GAGCATGCTTGGGGCCATCCAGCAGCTGCAGCAGAGGGGAC
Gln49TermATGAAATAGTTGTCCTAGCACCTGACGCCTCGTTGTACA
CAG-TAGTGTACAACGAGGCGTCAGGTGCTAGGACAACTATTTCATGTC3965
CCCTCTGCTGCAGCTGCTGGATGGCCCCAAGCATGCTCAGC
CAGTGGCTGCCATCCACTGGGATCAACAGTATCTTCCC
GGGCCATCCAGCAGCTG3966
CAGCTGCTGGATGGCCC3967
Crigler-Najjar syndromeCAGCAGAGGGGACATGAAATAGTTGTCCTAGCACCTGACGCC3968
1TCGTTGTACATCAGAGACGGAGCATTTTACACCTTGAAGACGT
Gly71ArgACCCTGTGCCATTCCAAAGGGAGGATGTGAAAGAGT
GGA-AGAACTCTTTCACATCCTCCCTTTGGAATGGCACAGGGTACGTCTT3969
CAAGGTGTAAAATGCTCCGTCTCTGATGTACAACGAGGCGTC
AGGTGCTAGGACAACTATTTCATGTCCCCTCTGCTG
TCAGAGACGGAGCATTT3970
AAATGCTCCGTCTCTGA3971
Gilbert syndromeGGGTGAAGAACATGCTCATTGCCTTTTCACAGAACTTTCTGTG3972
Pro229GlnCGACGTGGTTTATTCCCCGTATGCAACCCTTGCCTCAGAATT
CCG-CAGCCTTCAGAGAGAGGTGACTGTCCAGGACCTATTGAG
CTCAATAGGTCCTGGACAGTCACCTCTCTCTGAAGGAATTCT3973
GAGGCAAGGGTTGCATACGGGGAATAAACCACGTCGCACAG
AAAGTTCTGTGAAAAGGCAATGAGCATGTTCTTCACCC
TTATTCCCCGTATGCAA3974
TTGCATACGGGGAATAA3975
Crigler-Najjar syndromeTGTGAAGGATTACCCTAGGCCCATCATGCCCAATATGGTTTTT3976
1GTTGGTGGAATCAACTGCCTTCACCAAAATCCACTATCCCAG
Cys280TermGTGTGTATTGGAGTGGGACTTTTACATGCGTATATT
TGC-TGAAAT ACGCATGTAAAAGTCCCACTCCAATACACACCTGGGAT3977
AGTGGATTTTGGTGAAGGCAGTTGATTCCACCAACAAAAACC
ATATTGGGCATGATGGGCCTAGGGTAATCCTTCACA
ATCAACTGCCTTCACCA3978
TGGTGAAGGCAGTTGAT3979
Crigler-Najjar syndromeATCAAAGAATATGAGAAAAAATTAACTGAAAATTTTTCTTCTGG3980
1CTCTAGGAATTTGAAGCCTACATTAATGCTTCTGGAGAACATG
Ala292ValGAATTGTGGTTTTCTCTTTGGGATCAATGGTCTC
GCC-GTCGAGACCATTGATCCCAAAGAGAAAACCACAATTCCATGTTCTC3981
CAGAAGCATTAATGTAGGCTTCAAATTCCTAGAGCCAGAAGAA
AAATTTTCAGTTAATTTTTTCTCATATTCTTTGAT
ATTTGAAGCCTACATTA3982
TAATGTAGGCTTCAAAT3983
Crigler-Najjar syndromeAGGAATTTGAAGCCTACATTAATGCTTCTGGAGAACATGGAAT3984
1TGTGGTTTTCTCTTTGGGATCAATGGTCTCAGAAATTCCAGAG
Gly308GluAAGAAAGCTATGGCAATTGCTGATGCTTTGGGCAA
GGA-GAATTGCCCAAAGCATCAGCAATTGCCATAGCTTTCTTCTCTGGAA3985
TTTCTGAGACCATTGATCCCAAAGAGAAAACCACAATTCCATG
TTCTCCAGAAGCATTAATGTAGGCTTCAAATTCCT
CTCTTTGGGATCAATGG3986
CCATTGATCCCAAAGAG3987
Crigler-Najjar syndromeGTCTCAGAAATTCCAGAGAAGAAAGCTATGGCAATTGCTGAT3988
1GCTTTGGGCAAAATCCCTCAGACAGTAAGAAGATTCTATACCA
Gln331TermTGGCCTCATATCTATTTTCACAGGAGCGCTAATCCC
CAG-TAGGGGATTAGCGCTCCTGTGAAAATAGATATGAGGCCATGGTAT3989
AGAATCTTCTTACTGTCTGAGGGATTTTGCCCAAAGCATCAGC
AATTGCCATAGCTTTCTTCTCTGGAATTTCTGAGAC
AAATCCCTCAGACAGTA3990
TACTGTCTGAGGGATTT3991
Crigler-Najjar syndromeTCTAATCATATTATGTTCTTTCTTTACGTTCTGCTCTTTTTGCC3992
1CCTCCCAGGTCCTGTGGCGGTACACTGGAACCCGACCATCG
Trp335TermAATCTTGCGAACAACACGATACTTGTTAAGTGGCTA
TGG-TGATAGCCACTTAACAAGTATCGTGTTGTTCGCAAGATTCGATGGT3993
CGGGTTCCAGTGTACCGCCACAGGACCTGGGAGGGGCAAAA
AGAGCAGAACGTAAAGAAAGAACATAATATGATTAGA
GTCCTGTGGCGGTACAC3994
GTGTACCGCCACAGGAC3995
Crigler-Najjar syndromeACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATAC3996
1TTGTTAAGTGGCTACCCCAAAACGATCTGCTTGGTATGTTGG
Gln357ArgGCGGATTGGATGTATAGGTCAAACCAGGGTCAAATTA
CAA-CGATAATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACA3997
TACCAAGCAGATCGTTTTGGGGTAGCCACTTAACAAGTATCGT
GTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGT
GCTACCCCAAAACGATC3998
GATCGTTTTGGGGTAGC3999
Crigler-Najjar syndromeTACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATA4000
1CTTGTTAAGTGGCTACCCCAAAACGATCTGCTTGGTATGTTG
Gln357TermGGCGGATTGGATGTATAGGTCAAACCAGGGTCAAATT
CAA-TAAAATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACAT4001
ACCAAGCAGATCGTTTTGGGGTAGCCACTTAACAAGTATCGT
GTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGTA
GGCTACCCCAAAACGAT4002
ATCGTTTTGGGGTAGCC4003
Gilbert syndromeAACTCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCT4004
Arg367GlyCAGGTCACCCGATGACCCGTGCCTTTATCACCCATGCTGGTT
CGT-GGTCCCATGGTGTTTATGAAAGCATATGCAATGGCGTTC
GAACGCCATTGCATATGCTTTCATAAACACCATGGGAACCAG4005
CATGGGTGATAAAGGCACGGGTCATCGGGTGACCTGAGATG
CAAAATAGGGAGGATGTCAGCAGTTACATCTCTGAGTT
CGATGACCCGTGCCTTT4006
AAAGGCACGGGTCATCG4007
Crigler-Najjar syndromeTCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCTCAG4008
1GTCACCCGATGACCCGTGCCTTTATCACCCATGCTGGTTCCC
Ala368ThrATGGTGTTTATGAAAGCATATGCAATGGCGTTCCCA
GCC-ACCTGGGAACGCCATTGCATATGCTTTCATAAACACCATGGGAAC4009
CAGCATGGGTGATAAAGGCACGGGTCATCGGGTGACCTGAG
ATGCAAAATAGGGAGGATGTCAGCAGTTACATCTCTGA
TGACCCGTG CCTTTATC4010
GATAAAGGC ACGGGTCA4011
Crigler-Najjar syndromeCCTCCCTATTTTGCATCTCAGGTCACCCGATGACCCGTGCCT4012
1TTATCACCCATGCTGGTTCCCATGGTGTTTATGAAAGCATATG
Ser375PheCAATGGCGTTCCCATGGTGATGATGCCCTTGTTTGG
TCC-TTCCCAAACAAGGGCATCATCACCATGGGAACGCCATTGCATATG4013
CTTTCATAAACACCATGGGAACCAGCATGGGTGATAAAGGCA
CGGGTCATCGGGTGACCTGAGATGCAAAATAGGGAGG
TGCTGGTTCCCATGGTG4014
CACCATGGGAACCAGCA4015
Crigler-Najjar syndromeAGGTCACCCGATGACCCGTGCCTTTATCACCCATGCTGGTTC4016
1CCATGGTGTTTATGAAAGCATATGCAATGGCGTTCCCATGGT
Ser381ArgGATGATGCCCTTGTTTGGTGATCAGATGGACAATGCA
AGC-AGGTGCATTGTCCATCTGATCACCAAACAAGGGCATCATCACCAT4017
GGGAACGCCATTGCATATGCTTTCATAAACACCATGGGAACC
AGCATGGGTGATAAAGGCACGGGTCATCGGGTGACCT
TATGAAAGCATATGCAA4018
TTGCATATGCTTTCATA4019
Crigler-Najjar syndromeAGCATATGCAATGGCGTTCCCATGGTGATGATGCCCTTGTTT4020
1GGTGATCAGATGGACAATGCAAAGCGCATGGAGACTAAGGG
Ala401ProAGCTGGAGTGACCCTGAATGTTCTGGAAATGACTTCTG
GCA-CCACAGAAGTCATTTCCAGAACATTCAGGGTCACTCCAGCTCCCT4021
TAGTCTCCATGCGCTTTGCATTGTCCATCTGATCACCAAACAA
GGGCATCATCACCATGGGAACGCCATTGCATATGCT
TGGACAATGCAAAGCGC4022
GCGCTTTGCATTGTCCA4023
Crigler-Najjar syndromeGGAGCTGGAGTGACCCTGAATGTTCTGGAAATGACTTCTGAA4024
1GATTTAGAAAATGCTCTAAAAGCAGTCATCAATGACAAAAGGT
Lys428GluAAGAAAGAAGATACAGAAGAATACTTTGGTCATGGC
AAA-GAAGCCATGACCAAAGTATTCTTCTGTATCTTCTTTCTTACCTTTTG4025
TCATTGATGACTGCTTTTAGAGCATTTTCTAAATCTTCAGAAGT
CATTTCCAGAACATTCAGGGTCACTCCAGCTCC
ATGCTCTAAAAGCAGTC4026
GACTGCTTTTAGAGCAT4027
Crigler-Najjar syndromeATGAGGCACAAGGGCGCGCCACACCTGCGCCCCGCAGCCC4028
1ACGACCTCACCTGGTACCAGTACCATTCCTTGGACGTGATTG
Tyr486AspGTTTCCTCTTGGCCGTCGTGCTGACAGTGGCCTTCATCA
TAC-GACTGATGAAGGCCACTGTCAGCACGACGGCCAAGAGGAAACCA4029
ATCACGTCCAAGGAATGGTACTGGTACCAGGTGAGGTCGTG
GGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGTGCCTCAT
GGTACCAGTACCATTCC4030
GGAATGGTACTGGTACC4031
Crigler-Najjar syndromeACAAGGGCGCGCCACACCTGCGCCCCGCAGCCCACGACCT4032
1CACCTGGTACCAGTACCATTCCTTGGACGTGATTGGTTTCCT
Ser488PheCTTGGCCGTCGTGCTGACAGTGGCCTTCATCACCTTTAA
TCC-TTCTTAAAGGTGATGAAGGCCACTGTCAGCACGACGGCCAAGAG4033
GAAACCAATCACGTCCAAGGAATGGTACTGGTACCAGGTGAG
GTCGTGGGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGT
GTACCATTCCTTGGACG4034
CGTCCAAGGAATGGTAC4035
|
Alzheimer's Disease—Amyloid Precursor Protein (APP)
[0149] Over the past few decades Alzheimer's disease (AD), once considered a rare disorder, has become recognized as a major public health problem. Although there is no agreement on the exact prevalence of Alzheimer's disease, in part due to difficulties of diagnosis, studies consistently point to an exponential rise in prevalence of this disease with age. After age 65, the percentage of affected people approximately doubles with every decade of life, regardless of definition. Among people age 85 or loder, studies suggest that 25 to 35 percent have dementia, including Alzheimer's disease; one study reports that 47.2 percent of people over age 85 have Alzheimer's disease, exclusive of other dementias.
[0150] Alzheimer's disease progressively destroys memory, reason, judgment, language, and, eventually, the ability to carry out even the simplest tasks. Anatomic changes associated with Alzheimer's disease begin in the entorhinal cortex, procees to the hippocampus, and then gradually spread to other regions, particularly the cerebral cortex. Chief among such anatomic changes are the presence of characteristic extracellular plaques and internal neureofibriillary tangles.
[0151] At least four genes have been identified to date that contribute to development of Alzheimer's disease: AD1 is caused by mutations in the amyloid precursor gene (APP); AD2 is associated with a particular allele of APOE (see Example 20); AD3 is caused by mutation in a gene encoding a 7-transmembrane domain protein, presenilin-1 (PSEN1), and AD4 is caused by mutation in a gene that encodes a similar 7-transmembrane domain protein, presenilin-2 (PSEN2). The attached table discloses the correcting oligonucleotide base sequences for the APP oligonucleotides of the invention.
31TABLE 30
|
|
APP Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Alzheimer diseaseCTGCATACTTTAATTATGATGTAATACAGGTTCTGGGTTGACA4036
Glu665AspAATATCAAGACGGAGGAGATCTCTGAAGTGAAGATGGATGCA
GAG-GACGAATTCCGACATGACTCAGGATATGAAGTTCATCAT
ATGATGAACTTCATATCCTGAGTCATGTCGGAATTCTGCATCC4037
ATCTTCACTTCAGAGATCTCCTCCGTCTTGATATTTGTCAACC
CAGAACCTGTATTACATCATAATTAAAGTATGCAG
ACGGAGGAGATCTCTGA4038
TCAGAGATCTCCTCCGT4039
Alzheimer diseaseATTATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTT4040
Ala692GlyCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGTGC
GCA-GGAAATCATTGGACTCATGGTGGGCGGTGTTGTCAT
ATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTTTG4041
TTTGAACCCACATCTTCTGCAAAGAACACCTTGAAAACAAATT
AAGAAAAAGAATTTTAATTTCTAAATGCAATATAAT
GTTCTTTGCAGAAGATG4042
CATCTTCTGCAAAGAAC4043
Alzheimer diseaseTATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTC4044
Glu693GlnAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGTGCA
GAA-CAAATCATTGGACTCATGGTGGGCGGTGTTGTCATAG
CTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTT4045
TGTTTGAACCCACATCTTCTGCAAAGAACACCTTGAAAACAAA
TTAAGAAAAAGAATTTTAATTTCTAAATGCAATATA
TCTTTGCAGAAGATGTG4046
CACATCTTCTGCAAAGA4047
Alzheimer diseaseATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTCA4048
Glu693GlyAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGTGCAA
GAA-GGATCATTGGACTCATGGTGGGCGGTGTTGTCATAGC
GCTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCT4049
TTGTTTGAACCCACATCTTCTGCAAAGAACACCTTGAAAACAA
ATTAAGAAAAAGAATTTTAATTTCTAAATGCAATAT
CTTTGCAGAAGATGTGG4050
CCACATCTTCTGCAAAG4051
Alzheimer diseaseGAAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATG4052
Ala713ThrGTGGGCGGTGTTGTCATAGCGACAGTGATCGTCATCACCTTG
GCG-ACGGTGATGCTGAAGAAGAAACAGTACACATCCATTCATC
GATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGGT4053
GATGACGATCACTGTCGCTATGACAACACCGCCCACCATGAG
TCCAATGATTGCACCTTTGTTTGAACCCACATCTTC
TTGTCATAGCGACAGTG4054
CACTGTCGCTATGACAA4055
SchizophreniaAAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATGG4056
Ala713ValTGGGCGGTGTTGTCATAGCGACAGTGATCGTCATCACCTTGG
GCG-GTGTGATGCTGAAGAAGAAACAGTACACATCCATTCATCA
TGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGG4057
TGATGACGATCACTGTCGCTATGACAACACCGCCCACCATGA
GTCCAATGATTGCACCTTTGTTTGAACCCACATCTT
TGTCATAGCGACAGTGA4058
TCACTGTCGCTATGACA4059
Alzheimer diseaseGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGC4060
Val715MetGGTGTTGTCATAGCGACAGTGATCGTCATCACCTTGGTGATG
GTG-ATGCTGAAGAAGAAACAGTACACATCCATTCATCATGGTG
CACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCAC4061
CAAGGTGATGACGATCACTGTCGCTATGACAACACCGCCCAC
CATGAGTCCAATGATTGCACCTTTGTTTGAACCCAC
TAGCGACAGTGATCGTC4062
GACGATCACTGTCGCTA4063
Alzheimer diseaseGGTTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGT4064
Ile716ValGTTGTCATAGCGACAGTGATCGTCATCACCTTGGTGATGCTG
ATC-GTCAAGAAGAAACAGTACACATCCATTCATCATGGTGTGG
CCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCAT4065
CACCAAGGTGATGACGATCACTGTCGCTATGACAACACCGCC
CACCATGAGTCCAATGATTGCACCTTTGTTTGAACC
CGACAGTGATCGTCATC4066
GATGACGATCACTGTCG4067
Alzheimer diseaseCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTTG4068
Val717GlyTCATAGCGACAGTGATCGTCATCACCTTGGTGATGCTGAAGA
GTC-GGCAGAAACAGTACACATCCATTCATCATGGTGTGGTGGA
TCCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCA4069
GCATCACCAAGGTGATGACGATCACTGTCGCTATGACAACAC
CGCCCACCATGAGTCCAATGATTGCACCTTTGTTTG
AGTGATCGTCATCACCT4070
AGGTGATGACGATCACT4071
Alzheimer diseaseTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTT4072
Val717IleGTCATAGCGACAGTGATCGTCATCACCTTGGTGATGCTGAAG
GTC-ATCAAGAAACAGTACACATCCATTCATCATGGTGTGGTGG
CCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG4073
CATCACCAAGGTGATGACGATCACTGTCGCTATGACAACACC
GCCCACCATGAGTCCAATGATTGCACCTTTGTTTGA
CAGTGATCGTCATCACC4074
GGTGATGACGATCACTG4075
Alzheimer diseaseTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTT4076
Val717PheGTCATAGCGACAGTGATCGTCATCACCTTGGTGATGCTGAAG
GTC-TTCAAGAAACAGTACACATCCATTCATCATGGTGTGGTGG
CCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG4077
CATCACCAAGGTGATGACGATCACTGTCGCTATGACAACACC
GCCCACCATGAGTCCAATGATTGCACCTTTGTTTGA
CAGTGATCGTCATCACC4078
GGTGATGACGATCACTG4079
Alzheimer diseaseTTGGACTCATGGTGGGCGGTGTTGTCATAGCGACAGTGATCG4080
Leu723ProTCATCACCTTGGTGATGCTGAAGAAGAAACAGTACACATCCAT
CTG-CCGTCATCATGGTGTGGTGGAGGTAGGTAAACTTGACTG
CAGTCAAGTTTACCTACCTCCACCACACCATGATGAATGGAT4081
GTGTACTGTTTCTTCTTCAGCATCACCAAGGTGATGACGATCA
CTGTCGCTATGACAACACCGCCCACCATGAGTCCAA
GGTGATGCTGAAGAAGA4082
TCTTCTTCAGCATCACC4083
|
Alzheimer's Disease—Presenilin-1 (PSEN1)
[0152] The attached table discloses the correcting oligonucleotide base sequences for the PSEN1 oligonucleotides of the invention.
32TABLE 31
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|
PSEN1 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Alzheimer diseaseCCCGGCAGGTGGTGGAGCAAGATGAGGAAGAAGATGAGGAG4084
Ala79ValCTGACATTGAAATATGGCGCCAAGCATGTGATCATGCTCTTTG
GCC-GTCTCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTAC
GTAGCCACGACCACCACCATGCAGAGAGTCACAGGGACAAA4085
GAGCATGATCACATGCTTGGCGCCATATTTCAATGTCAGCTC
CTCATCTTCTTCCTCATCTTGCTCCACCACCTGCCGGG
ATATGGCGCCAAGCATG4086
CATGCTTGGCGCCATAT4087
Alzheimer diseaseGTGGTGGAGCAAGATGAGGAAGAAGATGAGGAGCTGACATT4088
Val82LeuGAAATATGGCGCCAAGCATGTGATCATGCTCTTTGTCCCTGT
tGTG-CTGGACTCTCTGCATGGTGGTGGTCGTGGCTACCATTAAGT
ACTTAATGGTAGCCACGACCACCACCATGCAGAGAGTCACAG4089
GGACAAAGAGCATGATCACATGCTTGGCGCCATATTTCAATG
TCAGCTCCTCATCTTCTTCCTCATCTTGCTCCACCAC
CCAAGCATGTGATCATG4090
CATGATCACATGCTTGG4091
Alzheimer diseaseAAATATGGCGCCAAGCATGTGATCATGCTCTTTGTCCCTGTG4092
Val96PheACTCTCTGCATGGTGGTGGTCGTGGCTACCATTAAGTCAGTC
gGTC-TTCAGCTTTTATACCCGGAAGGATGGGCAGCTGTACGTAT
ATACGTACAGCTGCCCATCCTTCCGGGTATAAAAGCTGACTG4093
ACTTAATGGTAGCCACGACCACCACCATGCAGAGAGTCACAG
GGACAAAGAGCATGATCACATGCTTGGCGCCATATTT
TGGTGGTGGTCGTGGCT4094
AGCCACGACCACCACCA4095
Alzheimer diseaseCTTTGTCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTAC4096
Phe105LeuCATTAAGTCAGTCAGCTTTTATACCCGGAAGGATGGGCAGCT
TTTt-TTGGTACGTATGAGTTTTGTTTTATTATTCTCAAAGCCAG
CTGGCTTTGAGAATAATAAAACAAAACTCATACGTACAGCTGC4097
CCATCCTTCCGGGTATAAAAGCTGACTGACTTAATGGTAGCC
ACGACCACCACCATGCAGAGAGTCACAGGGACAAAG
GTCAGCTTTTATACCCG4098
CGGGTATAAAAGCTGAC4099
Alzheimer diseaseTGGTGATCTCCATTAACACTGACCTAGGGCTTTTGTGTTTGTT4100
Thr116AsnTTATTGTAGAATCTATACCCCATTCACAGAAGATACCGAGACT
ACC-AACGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGC
GCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTCG4101
GTATCTTCTGTGAATGGGGTATAGATTCTACAATAAAACAAAC
ACAAAAGCCCTAGGTCAGTGTTAATGGAGATCACCA
AATCTATACCCCATTCA4102
TGAATGGGGTATAGATT4103
Alzheimer diseaseTGATCTCCATTAACACTGACCTAGGGCTTTTGTGTTTGTTTTAT4104
Pro117LeuTGTAGAATCTATACCCCATTCACAGAAGATACCGAGACTGTG
CCA-CTAGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGC
GCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTC4105
TCGGTATCTTCTGTGAATGGGGTATAGATTCTACAATAAAACA
AACACAAAAGCCCTAGGTCAGTGTTAATGGAGATCA
CTATACCCCATTCACAG4106
CTGTGAATGGGGTATAG4107
Alzheimer diseaseTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT4108
Glu120AspATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAGAG
GAAg-GATCCCTGCACTCAATTCTGAATGCTGCCATCATGATC
GATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTG4109
GCCCACAGTCTCGGTATCTTCTGTGAATGGGGTATAGATTCT
ACAATAAAACAAACACAAAAGCCCTAGGTCAGTGTTA
TTCACAGAAGATACCGA4110
TCGGTATCTTCTGTGAA4111
Alzheimer diseaseTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT4112
Glu120AspATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAGAG
GAAg-GACCCCTGCACTCAATTCTGAATGCTGCCATCATGATC
GATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTG4113
GCCCACAGTCTCGGTATCTTCTGTGAATGGGGTATAGATTCT
ACAATAAAACAAACACAAAAGCCCTAGGTCAGTGTTA
TTCACAGAAGATACCGA4114
TCGGTATCTTCTGTGAA4115
Alzheimer diseaseATTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAAT4116
Glu120LysCTATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAG
aGAA-AAAAGCCCTGCACTCAATTCTGAATGCTGCCATCATGA
TCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGC4117
CCACAGTCTCGGTATCTTCTGTGAATGGGGTATAGATTCTACA
ATAAAACAAACACAAAAGCCCTAGGTCAGTGTTAAT
CATTCACAGAAGATACC4118
GGTATCTTCTGTGAATG4119
Alzheimer diseaseGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCTATACCC4120
Glu123LysCATTCACAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTG
cGAG-AAGCACTCAATTCTGAATGCTGCCATCATGATCAGTGTCA
TGACACTGATCATGATGGCAGCATTCAGAATTGAGTGCAGGG4121
CTCTCTGGCCCACAGTCTCGGTATCTTCTGTGAATGGGGTAT
AGATTCTACAATAAAACAAACACAAAAGCCCTAGGTC
AAGATACCGAGACTGTG4122
CACAGTCTCGGTATCTT4123
Alzheimer diseaseTATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAGA4124
Asn135AspGCCCTGCACTCAATTCTGAATGCTGCCATCATGATCAGTGTC
gAAT-GATATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTATA
TATACAGAACCACCAGGAGGATAGTCATGACAACAATGACAC4125
TGATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCT
GGCCCACAGTCTCGGTATCTTCTGTGAATGGGGTATA
CAATTCTGAATGCTGCC4126
GGCAGCATTCAGAATTG4127
Alzheimer diseaseAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCAA4128
Met139IleTTCTGAATGCTGCCATCATGATCAGTGTCATTGTTGTCATGAC
ATGa-ATATATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTAT
ATAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATG4129
ACAACAATGACACTGATCATGATGGCAGCATTCAGAATTGAGT
GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCT
GCCATCATGATCAGTGT4130
ACACTGATCATGATGGC4131
Alzheimer diseaseCAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA4132
Met139LysATTCTGAATGCTGCCATCATGATCAGTGTCATTGTTGTCATGA
ATG-AAGCTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTA
TAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA4133
CAACAATGACACTGATCATGATGGCAGCATTCAGAATTGAGT
GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG
TGCCATCATGATCAGTG4134
CACTGATCATGATGGCA4135
Alzheimer diseaseCAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA4136
Met139ThrATTCTGAATGCTGCCATCATGATCAGTGTCATTGTTGTCATGA
ATG-ACGCTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTA
TAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA4137
CAACAATGACACTGATCATGATGGCAGCATTCAGAATTGAGT
GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG
TGCCATCATGATCAGTG4138
CACTGATCATGATGGCA4139
Alzheimer diseaseACAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTC4140
Met139ValAATTCTGAATGCTGCCATCATGATCAGTGTCATTGTTGTCATG
cATG-GTGACTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCT
AGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA4141
CAACAATGACACTGATCATGATGGCAGCATTCAGAATTGAGT
GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTGT
CTGCCATCATGATCAGT4142
ACTGATCATGATGGCAG4143
Alzheimer diseaseGAGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCT4144
Ile143PheGCCATCATGATCAGTGTCATTGTTGTCATGACTATCCTCCTGG
cATT-TTTTGGTTCTGTATAAATACAGGTGCTATAAGGTGAGCA
TGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGAG4145
GATAGTCATGACAACAATGACACTGATCATGATGGCAGCATTC
AGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTC
TCAGTGTCATTGTTGTC4146
GACAACAATGACACTGA4147
Alzheimer diseaseAGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTG4148
Ile143ThrCCATCATGATCAGTGTCATTGTTGTCATGACTATCCTCCTGGT
ATT-ACTGGTTCTGTATAAATACAGGTGCTATAAGGTGAGCAT
ATGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGA4149
GGATAGTCATGACAACAATGACACTGATCATGATGGCAGCAT
TCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCT
CAGTGTCATTGTTGTCA4150
TGACAACAATGACACTG4151
Alzheimer diseaseCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGAT4152
Met146IleCAGTGTCATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTAT
ATGa-ATAAAATACAGGTGCTATAAGGTGAGCATGAGACACAGA
TCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA4153
ACCACCAGGAGGATAGTCATGACAACAATGACACTGATCATG
ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG
GTTGTCATGACTATCCT4154
AGGATAGTCATGACAAC4155
Alzheimer diseaseCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGAT4156
Met146IleCAGTGTCATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTAT
ATGa-ATCAAATACAGGTGCTATAAGGTGAGCATGAGACACAGA
TCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA4157
ACCACCAGGAGGATAGTCATGACAACAATGACACTGATCATG
ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG
GTTGTCATGACTATCCT4158
AGGATAGTCATGACAAC4159
Alzheimer diseaseGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATG4160
Met146LeuATCAGTGTCATTGTTGTCATGACTATCCTCCTGGTGGTTCTGT
cATG-TTGATAAATACAGGTGCTATAAGGTGAGCATGAGACACA
TGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGAAC4161
CACCAGGAGGATAGTCATGACAACAATGACACTGATCATGAT
GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC
TTGTTGTCATGACTATC4162
GATAGTCATGACAACAA4163
Alzheimer diseaseGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATG4164
Met146ValATCAGTGTCATTGTTGTCATGACTATCCTCCTGGTGGTTCTGT
cATG-GTGATAAATACAGGTGCTATAAGGTGAGCATGAGACACA
TGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGAAC4165
CACCAGGAGGATAGTCATGACAACAATGACACTGATCATGAT
GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC
TTGTTGTCATGACTATC4166
GATAGTCATGACAACAA4167
Alzheimer diseaseAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGATCA4168
Thr147IleGTGTCATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTATAA
ACT-ATTATACAGGTGCTATAAGGTGAGCATGAGACACAGATC
GATCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACA4169
GAACCACCAGGAGGATAGTCATGACAACAATGACACTGATCA
TGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCT
TGTCATGACTATCCTCC4170
GGAGGATAGTCATGACA4171
Alzheimer diseaseCTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTT4172
His163ArgCTTTTCTAGGTCATCCATGCCTGGCTTATTATATCATCTCTATT
CAT-CGTGTTGCTGTTCTTTTTTTCATTCATTTACTTGGG
CCCAAGTAAATGAATGAAAAAAAGAACAGCAACAATAGAGATG4173
ATATAATAAGCCAGGCATGGATGACCTAGAAAAGAAAGCATTT
CAATATAATTAACAGGTCCCACAACCCTTAAAAAG
GGTCATCCATGCCTGGC4174
GCCAGGCATGGATGACC4175
Alzheimer diseaseACTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTT4176
His163TyrTCTTTTCTAGGTCATCCATGCCTGGCTTATTATATCATCTCTAT
cCAT-TATTGTTGCTGTTCTTTTTTTCATTCATTTACTTGG
CCAAGTAAATGAATGAAAAAAAGAACAGCAACAATAGAGATGA4177
TATAATAAGCCAGGCATGGATGACCTAGAAAAGAAAGCATTTC
AATATAATTAACAGGTCCCACAACCCTTAAAAAGT
AGGTCATCCATGCCTGG4178
CCAGGCATGGATGACCT4179
Aizheimer diseaseAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTTCTTTTCT4180
Trp165CysAGGTCATCCATGCCTGGCTTATTATATCATCTCTATTGTTGCT
TGGc-TGCGTTCTTTTTTTCATTCATTTACTTGGGGTAAGTT
AACTTACCCCAAGTAAATGAATGAAAAAAAGAACAGCAACAAT4181
AGAGATGATATAATAAGCCAGGCATGGATGACCTAGAAAAGA
AAGCATTTCAATATAATTAACAGGTCCCACAACCCT
CATGCCTGGCTTATTAT4182
ATAATAAGCCAGGCATG4183
Alzheimer diseaseACCTGTTAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCAT4184
Ser169LeuGCCTGGCTTATTATATCATCTCTATTGTTGCTGTTCTTTTTTTC
TCA-TTAATTCATTTACTTGGGGTAAGTTGTGAAATTTTT
AAAAATTTCACAACTTACCCCAAGTAAATGAATGAAAAAAAGAA4185
CAGCAACAATAGAGATGATATAATAAGCCAGGCATGGATGAC
CTAGAAAAGAAAGCATTTCAATATAATTAACAGGT
TATTATATCATCTCTAT4186
ATAGAGATGATATAATA4187
Alzheimer diseaseTAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGG4188
Leu171ProCTTATTATATCATCTCTATTGTTGCTGTTCTTTTTTTCATTCATT
CTA-CCATACTTGGGGTAAGTTGTGAAATTTTTGGTCTG
CAGACCAAAAATTTCACAACTTACCCCAAGTAAATGAATGAAA4189
AAAAGAACAGCAACAATAGAGATGATATAATAAGCCAGGCAT
GGATGACCTAGAAAAGAAAGCATTTCAATATAATTA
ATCATCTCTATTGTTGC4190
GCAACAATAGAGATGAT4191
Alzheimer diseaseTATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGGCTTATT4192
Leu173TrpATATCATCTCTATTGTTGCTGTTCTTTTTTTCATTCATTTACTTG
TTG-TGGGGGTAAGTTGTGAAATTTTTGGTCTGTCTTTC
GAAAGACAGACCAAAAATTTCACAACTTACCCCAAGTAAATGA4193
ATGAAAAAAAGAACAGCAACAATAGAGATGATATAATAAGCCA
GGCATGGATGACCTAGAAAAGAAAGCATTTCAATA
TCTATTGTTGCTGTTCT4194
AGAACAGCAACAATAGA4195
Alzheimer diseaseTATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCT4196
Gly209ArgGGAATTTTGGTGTGGTGGGAATGATTTCCATTCACTGGAAAG
gGGA-AGAGTCCACTTCGACTCCAGCAGGCATATCTCATTATGA
TCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC4197
AGTGAATGGAAATCATTCCCACCACACCAAAATTCCAGATCAG
GAGTGCAACAGTAATGTAGTCCACAGCAACGTTATA
GTGTGGTGGGAATGATT4198
AATCATTCCCACCACAC4199
Alzheimer diseaseATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCTG4200
Gly209ValGAATTTTGGTGTGGTGGGAATGATTTCCATTCACTGGAAAGGT
GGA-GTACCACTTCGACTCCAGCAGGCATATCTCATTATGAT
ATCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTC4201
CAGTGAATGGAAATCATTCCCACCACACCAAAATTCCAGATCA
GGAGTGCAACAGTAATGTAGTCCACAGCAACGTTAT
TGTGGTGGGAATGATTT4202
AAATCATTCCCACCACA4203
Alzheimer diseaseTGGACTACATTACTGTTGCACTCCTGATCTGGAATTTTGGTGT4204
Ile213ThrGGTGGGAATGATTTCCATTCACTGGAAAGGTCCACTTCGACT
ATT-ACTCCAGCAGGCATATCTCATTATGATTAGTGCCCTCAT
ATGAGGGCACTAATCATAATGAGATATGCCTGCTGGAGTCGA4205
AGTGGACCTTTCCAGTGAATGGAAATCATTCCCACCACACCA
AAATTCCAGATCAGGAGTGCAACAGTAATGTAGTCCA
GATTTCCATTCACTGGA4206
TCCAGTGAATGGAAATC4207
Alzheimer diseaseCACTCCTGATCTGGAATTTTGGTGTGGTGGGAATGATTTCCAT4208
Leu219ProTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCAT
CTT-CCTTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAA
TTGATAAACACCAGGGCCATGAGGGCACTAATCATAATGAGA4209
TATGCCTGCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAA
ATCATTCCCACCACACCAAAATTCCAGATCAGGAGTG
AGGTCCACTTCGACTCC4210
GGAGTCGAAGTGGACCT4211
Alzheimer diseaseATTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCA4212
Ala231ThrTATCTCATTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCA
tGCC-ACCAGTACCTCCCTGAATGGACTGCGTGGCTCATCTTGG
CCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATAA4213
ACACCAGGGCCATGAGGGCACTAATCATAATGAGATATGCCT
GCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAAT
TGATTAGTGCCCTCATG4214
CATGAGGGCACTAATCA4215
Alzheimer diseaseTTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCAT4216
Ala231ValATCTCATTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAA
GCC-GTCGTACCTCCCTGAATGGACTGCGTGGCTCATCTTGGC
GCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATA4217
AACACCAGGGCCATGAGGGCACTAATCATAATGAGATATGCC
TGCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAA
GATTAGTGCCCTCATGG4218
CCATGAGGGCACTAATC4219
Alzheimer diseaseTTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCA4220
Met233ThrTTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAAGTACCT
ATG-ACGCCCTGAATGGACTGCGTGGCTCATCTTGGCTGTGAT
ATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTAC4221
TTGATAAACACCAGGGCCATGAGGGCACTAATCATAATGAGA
TATGCCTGCTGGAGTCGAAGTGGACCTTTCCAGTGAA
TGCCCTCATGGCCCTGG4222
CCAGGGCCATGAGGGCA4223
Alzheimer diseaseGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCATTATGA4224
Leu235ProTTAGTGCCCTCATGGCCCTGGTGTTTATCAAGTACCTCCCTG
CTG-CCGAATGGACTGCGTGGCTCATCTTGGCTGTGATTTCAGT
ACTGAAATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGG4225
AGGTACTTGATAAACACCAGGGCCATGAGGGCACTAATCATA
ATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC
CATGGCCCTGGTGTTTA4226
TAAACACCAGGGCCATG4227
Alzheimer diseaseTCATTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAAGTA4228
Ala246GluCCTCCCTGAATGGACTGCGTGGCTCATCTTGGCTGTGATTTC
GCG-GAGAGTATATGGTAAAACCCAAGACTGATAATTTGTTTG
CAAACAAATTATCAGTCTTGGGTTTTACCATATACTGAAATCAC4229
AGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGAT
AAACACCAGGGCCATGAGGGCACTAATCATAATGA
ATGGACTGCGTGGCTCA4230
TGAGCCACGCAGTCCAT4231
Alzheimer diseaseGTGCCCTCATGGCCCTGGTGTTTATCAAGTACCTCCCTGAAT4232
Leu250SerGGACTGCGTGGCTCATCTTGGCTGTGATTTCAGTATATGGTA
TTG-TCGAAACCCAAGACTGATAATTTGTTTGTCACAGGAATGC
GCATTCCTGTGACAAACAAATTATCAGTCTTGGGTTTTACCAT4233
ATACTGAAATCACAGCCAAGATGAGCCACGCAGTCCATTCAG
GGAGGTACTTGATAAACACCAGGGCCATGAGGGCAC
GCTCATCTTGGCTGTGA4234
TCACAGCCAAGATGAGC4235
Alzheimer diseaseAGTTTAGCCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTT4236
Ala260ValTTCTAGATTTAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCG
GCT-GTTTATGCTGGTTGAAACAGCTCAGGAGAGAAATGA
TCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGAAGTGGAC4237
CTTTCGGACACAAAACAGCCACTAAATCTAGAAAAAGAAAAAC
ATAAAAGACATCTAATAAAATGTATGGGCTAAACT
TTTAGTGGCTGTTTTGT4238
ACAAAACAGCCACTAAA4239
Alzheimer diseaseCCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGA4240
Leu262PheTTTAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTG
TTGt-TTCGTTGAAACAGCTCAGGAGAGAAATGAAACGCTT
AAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGA4241
AGTGGACCTTTCGGACACAAAACAGCCACTAAATCTAGAAAAA
GAAAAACATAAAAGACATCTAATAAAATGTATGGG
GCTGTTTTGTGTCCGAA4242
TTCGGACACAAAACAGC4243
Alzheimer diseaseCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGAT4244
Cys263ArgTTAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTG
gTGT-CGTGTTGAAACAGCTCAGGAGAGAAATGAAACGCTTT
AAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACG4245
AAGTGGACCTTTCGGACACAAAACAGCCACTAAATCTAGAAA
AAGAAAAACATAAAAGACATCTAATAAAATGTATGG
CTGTTTTGTGTCCGAAA4246
TTTCGGACACAAAACAG4247
Alzheimer diseaseACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGATTTAG4248
Pro264LeuTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTG
CCG-CTGAAACAGCTCAGGAGAGAAATGAAACGCTTTTTCC
GGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCA4249
TACGAAGTGGACCTTTCGGACACAAAACAGCCACTAAATCTA
GAAAAAGAAAAACATAAAAGACATCTAATAAAATGT
TTTGTGTCCGAAAGGTC4250
GACCTTTCGGACACAAA4251
Alzheimer diseaseGTCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTG4252
Arg269GlyTCCGAAAGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGA
tCGT-CCTGAGAAATGAAACGCTTTTTCCAGCTCTCATTTACT
AGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAGC4253
TGTTTCAACCAGCATACGAAGTGGACCTTTCGGACACAAAAC
AGCCACTAAATCTAGAAAAAGAAAAACATAAAAGAC
GTCCACTTCGTATGCTG4254
CAGCATACGAAGTGGAC4255
Alzheimer diseaseTCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTGTC4256
Arg269HisCGAAAGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGA
CGT-CATGAAATGAAACGCTTTTTCCAGCTCTCATTTACTC
GAGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAG4257
CTGTTTCAACCAGCATACGAAGTGGACCTTTCGGACACAAAA
CAGCCACTAAATCTAGAAAAAGAAAAACATAAAAGA
TCCACTTCGTATGCTGG4258
CCAGCATACGAAGTGGA4259
Alzheimer diseaseTAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGG4260
Arg278ThrTTGAAACAGCTCAGGAGAGAAATGAAACGCTTTTTCCAGCTCT
AGA-ACACATTTACTCCTGTAAGTATTTGAGAATGATATTGAA
TTCAATATCATTCTCAAATACTTACAGGAGTAAATGAGAGCTG4261
GAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCAT
ACGAAGTGGACCTTTCGGACACAAAACAGCCACTA
TCAGGAGAGAAATGAAA4262
TTTCATTTCTCTCCTGA4263
Alzheimer diseaseCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC4264
Glu280AlaAGCTCAGGAGAGAAATGAAACGCTTTTTCCAGCTCTCATTTAC
GAA-GCATCCTGTAAGTATTTGAGAATGATATTGAATTAGTA
TACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG4265
AGCTGGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACC
AGCATACGAAGTGGACCTTTCGGACACAAAACAG
GAGAAATGAAACGCTTT4266
AAAGCGTTTCATTTCTC4267
Alzheimer diseaseCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC4268
Glu280GlyAGCTCAGGAGAGAAATGAAACGCTTTTTCCAGCTCTCATTTAC
GAA-GGATCCTGTAAGTATTTGAGAATGATATTGAATTAGTA
TACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG4269
AGCTGGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACC
AGCATACGAAGTGGACCTTTCGGACACAAAACAG
GAGAAATGAAACGCTTT4270
AAAGCGTTTCATTTCTC4271
Alzheimer diseaseTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAACAGCTC4272
Leu282ArgAGGAGAGAAATGAAACGCTTTTTCCAGCTCTCATTTACTCCTG
CThCGTTAAGTATTTGAGAATGATATTGAATTAGTAATCAGT
ACTGATTACTAATTCAATATCATTCTCAAATACTTACAGGAGTA4273
AATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTT
TCAACCAGCATACGAAGTGGACCTTTCGGACACA
TGAAACGCTTTTTCCAG4274
CTGGAAAAAGCGTTTCA4275
Alzheimer diseaseAAGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAA4276
Ala285ValATGAAACGCTTTTTCCAGCTCTCATTTACTCCTGTAAGTATTTG
GCT-GTTAGAATGATATTGAATTAGTAATCAGTGTAGAATTT
AAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACTTA4277
CAGGAGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCT
GAGCTGTTTCAACCAGCATACGAAGTGGACCTT
TTTTCCAGCTCTCATTT4278
AAATGAGAGCTGGAAAA4279
Alzheimer diseaseGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAAAT4280
Leu286ValGAAACGCTTTTTCCAGCTCTCATTTACTCCTGTAAGTATTTGA
tCTC-GTCGAATGATATTGAATTAGTAATCAGTGTAGAATTTAT
ATAAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACT4281
TACAGGAGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTC
CTGAGCTGTTTCAACCAGCATACGAAGTGGACC
TTCCAGCTCTCATTTAC4282
GTAAATGAGAGCTGGAA4283
Alzheimer diseaseGTGACCAACTTTTTAATATTTGTAACCTTTCCTTTTTAGGGGGA4284
Gly384AlaGTAAAACTTGGATTGGGAGATTTCATTTTCTACAGTGTTCTGG
GGA-GCATTGGTAAAGCCTCAGCAACAGCCAGTGGAGACTG
CAGTCTCCACTGGCTGTTGCTGAGGCTTTACCAACCAGAACA4285
CTGTAGAAAATGAAATCTCCCAATCCAAGTTTTACTCCCCCTA
AAAAGGAAAGGTTACAAATATTAAAAAGTTGGTCAC
TGGATTGGGAGATTTCA4286
TGAAATCTCCCAATCCA4287
Alzheimer diseaseTTTGTAACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGG4288
Ser390IleAGATTTCATTTTCTACAGTGTTCTGGTTGGTAAAGCCTCAGCA
AGT-ATTACAGCCAGTGGAGACTGGAACACAACCATAGCCTG
CAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTGCTGAG4289
GCTTTACCAACCAGAACACTGTAGAAAATGAAATCTCCCAATC
CAAGTTTTACTCCCCCTAAAAAGGAAAGGTTACAAA
TTTCTACAGTGTTCTGG4290
CCAGAACACTGTAGAAA4291
Alzheimer diseaseAACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGGAGATT4292
Leu392ValTCATTTTCTACAGTGTTCTGGTTGGTAAAGCCTCAGCAACAGC
tCTG-GTGCAGTGGAGACTGGAACACAACCATAGCCTGTTTCG
CGAAACAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTG4293
CTGAGGCTTTACCAACCAGAACACTGTAGAAAATGAAATCTCC
CAATCCAAGTTTTACTCCCCCTAAAAAGGAAAGGTT
ACAGTGTTCTGGTTGGT4294
ACCAACCAGAACACTGT4295
Alzheimer diseaseATTTCATTTTCTACAGTGTTCTGGTTGGTAAAGCCTCAGCAAC4296
Asn405SerAGCCAGTGGAGACTGGAACACAACCATAGCCTGTTTCGTAGC
AAC-AGCCATATTAATTGTAAGTATACACTAATAAGAATGTGT
ACACATTCTTATTAGTGTATACTTACAATTAATATGGCTACGAA4297
ACAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTGCTGA
GGCTTTACCAACCAGAACACTGTAGAAAATGAAAT
AGACTGGAACACAACCA4298
TGGTTGTGTTCCAGTCT4299
Alzheimer diseaseTACAGTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGA4300
Ala409ThrGACTGGAACACAACCATAGCCTGTTTCGTAGCCATATTAATTG
aGCC-ACCTAAGTATACACTAATAAGAATGTGTCAGAGCTCTTA
TAAGAGCTCTGACACATTCTTATTAGTGTATACTTACAATTAAT4301
ATGGCTACGAAACAGGCTATGGTTGTGTTCCAGTCTCCACTG
GCTGTTGCTGAGGCTTTACCAACCAGAACACTGTA
CAACCATAGCCTGTTTC4302
GAAACAGGCTATGGTTG4303
Alzheimer diseaseGTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGAGACT4304
Cys410TyrGGAACACAACCATAGCCTGTTTCGTAGCCATATTAATTGTAAG
TGT-TATTATACACTAATAAGAATGTGTCAGAGCTCTTAATGT
ACATTAAGAGCTCTGACACATTCTTATTAGTGTATACTTACAAT4305
TAATATGGCTACGAAACAGGCTATGGTTGTGTTCCAGTCTCCA
CTGGCTGTTGCTGAGGCTTTACCAACCAGAACAC
CATAGCCTGTTTCGTAG4306
CTACGAAACAGGCTATG4307
Alzheimer diseaseTGTGAATGTGTGTCTTTCCCATCTTCTCCACAGGGTTTGTGCC4308
Ala426ProTTACATTATTACTCCTTGCCATTTTCAAGAAAGCATTGCCAGCT
tGCC-CCCCTTCCAATCTCCATCACCTTTGGGCTTGTTTTCT
AGAAAACAAGCCCAAAGGTGATGGAGATTGGAAGAGCTGGCA4309
ATGCTTTCTTGAAAATGGCAAGGAGTAATAATGTAAGGCACAA
ACCCTGTGGAGAAGATGGGAAAGACACACATTCACA
TACTCCTTGCCATTTTC4310
GAAAATGGCAAGGAGTA4311
Alzheimer diseaseAGGGTTTGTGCCTTACATTATTACTCCTTGCCATTTTCAAGAA4312
Pro436GlnAGCATTGCCAGCTCTTCCAATCTCCATCACCTTTGGGCTTGTT
CCA-CAATTCTACTTTGCCACAGATTATCTTGTACAGCCTTT
AAAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGC4313
CCAAAGGTGATGGAGATTGGAAGAGCTGGCAATGCTTTCTTG
AAAATGGCAAGGAGTAATAATGTAAGGCACAAACCCT
AGCTCTTCCAATCTCCA4314
TGGAGATTGGAAGAGCT4315
Alzheimer diseaseCAGGGTTTGTGCCTTACATTATTACTCCTTGCCATTTTCAAGA4316
Pro436SerAAGCATTGCCAGCTCTTCCAATCTCCATCACCTTTGGGCTTGT
tCCA-TCATTTCTACTTTGCCACAGATTATCTTGTACAGCCTT
AAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGCC4317
CAAAGGTGATGGAGATTGGAAGAGCTGGCAATGCTTTCTTGA
AAATGGCAAGGAGTAATAATGTAAGGCACAAACCCTG
CAGCTCTTCCAATCTCC4318
GGAGATTGGAAGAGCTG4319
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Alzheimer's Disease—Presenilin-2 (PSEN2)
[0153] The attached table discloses the correcting oligonucleotide base sequences for the PSEN2 oligonucleotides of the invention.
33TABLE 32
|
|
PSEN2 Mutations and Genome-Correcting Oligos
Clinical Phenotype &SEQ ID
MutationCorrecting OligosNO:
|
Alzheimer diseaseGATGTGGTTTCCCACAGAGAAGCCAGGAGAACGAGGAGGAC4320
Arg62HisGGTGAGGAGGACCCTGACCGCTATGTCTGTAGTGGGGTTCC
CGC-CACCGGGCGGCCGCCAGGCCTGGAGGAAGAGCTGACCCTCAA
TTGAGGGTCAGCTCTTCCTCCAGGCCTGGCGGCCGCCCGGG4321
AACCCCACTACAGACATAGCGGTCAGGGTCCTCCTCACCGTC
CTCCTCGTTCTCCTGGCTTCTCTGTGGGAAACCACATC
CCCTGACCGCTATGTCT4322
AGACATAGCGGTCAGGG4323
Alzheimer diseaseGCCTCGAGGAGCAGTCAGGGCCGGGAGCATCAGCCCTTTGC4324
Thr122ProCTTCTCCCTCAGCATCTACACGACATTCACTGAGGACACACC
cACG-CCGCTCGGTGGGCCAGCGCCTCCTCAACTCCGTGCTGAACA
TGTTCAGCACGGAGTTGAGGAGGCGCTGGCCCACCGAGGGT4325
GTGTCCTCAGTGAATGTCGTGTAGATGCTGAGGGAGAAGGCA
AAGGGCTGATGCTCCCGGCCCTGACTGCTCCTCGAGGC
GCATCTACACGACATTC4326
GAATGTCGTGTAGATGC4327
Alzheimer diseaseACACGCCATTCACTGAGGACACACCCTCGGTGGGCCAGCGC4328
Asn141IleCTCCTCAACTCCGTGCTGAACACCCTCATCATGATCAGCGTC
AAC-ATCATCGTGGTTATGACCATCTTCTTGGTGGTGCTCTACAA
TTGTAGAGCACCACCAAGAAGATGGTCATAACCACGATGACG4329
CTGATCATGATGAGGGTGTTCAGCACGGAGTTGAGGAGGCG
CTGGCCCACCGAGGGTGTGTCCTCAGTGAATGGCGTGT
CGTGCTGAACACCCTCA4330
TGAGGGTGTTCAGCACG4331
Alzheimer diseaseCCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCTCA4332
Met239IleTCATGATCAGTGCGCTCATGGCCCTAGTGTTCATCAAGTACCT
ATGg-ATACCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCATC
GATGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGT4333
ACTTGATGAACACTAGGGCCATGAGCGCACTGATCATGATGA
GGTAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGG
GCGCTCATGGCCCTAGT4334
ACTAGGGCCATGAGCGC4335
Alzheimer diseaseATCCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCT4336
Met239ValCATCATGATCAGTGCGCTCATGGCCCTAGTGTTCATCAAGTA
cATG-GTGCCTCCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCA
TGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGTAC4337
TTGATGAACACTAGGGCCATGAGCGCACTGATCATGATGAGG
TAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGGAT
GTGCGCTCATGGCCCTA4338
TAGGGCCATGAGCGCAC4339
|
Plant Cells
[0154] The oligonucleotides of the invention can also be used to repair or direct a mulagenic event in plants and animal cells. Although little information is available on plant mutations amongst natural cultivars, the oligonucleotides of the invention can be used to produce “knock out” mutations by modification of specific amino acid codons to produce stop codons (e.g., a CAA codon specifying Gln can be modified at a specific site to TAA; a AAG codon specifying Lys can be modified to UAG at a specific site; and a CGA codon for Arg can be modified to a UGA codon at a specific site). Such base pair changes will terminate the reading frame and produce a defective truncated protein, shortened at the site of the stop codon. Alternatively, frameshift additions or deletions can be directed into the genome at a specific sequence to interrupt the reading frame and produce a garbled downstream protein. Such stop or frameshift mutations can be introduced to determine the effect of knocking out the protein in either plant or animal cells.
[0155] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of oridinary skill in the art in light of the teachings of this invention that certain changes and modifications may by made thereto without departing from the spirit or scope of the appended claims.
Claims
- 1. An oligonucleotide for targeted alteration(s) of genetic sequence, comprising a single-stranded oligonucleotide having a DNA domain, said DNA domain having at least one mismatch with respect to the genetic sequence to be altered, and further comprising chemical modifications within the oligonucleotide, said targeted alteration(s) occurring more frequently than alteration(s) of the genetic sequence by a double-stranded double hairpin chimeric oligonucleotide containing RNA and DNA nucleotides.
- 2. The oligonucleotide according to claim one that comprises at least one phosphorothioate linkage within the oligonucleotide.
- 3. The oligonucleotide according to claim one that comprises a 2′-O-methyl analog.
- 4. The oligonucleotide according to claim one that comprises a locked nucleotide analog.
- 5. The oligonucleotide according to claim one that comprises a combination of at least two modifications selected from the group of a phosphorothioate linkage, a 2′-O-methyl analog, a locked nucleotide analog and a ribonucleotide.
- 6. The oligonucleotide according to any one of claims 1 to 5 that comprises at least one unmodified ribonucleotide.
- 7. The oligonucleotide according to any one of claims 1 to 6, wherein the sequence of said oligonucleotide is selected from the group consisting of SEQ ID NOS: 1-4339.
- 8. A method of targeted alteration of genetic material, comprising combining the target genetic material with an oligonucleotide according to any one of claims 1 to 7 in the presence of purified proteins.
- 9. A method of targeted alteration of genetic material, comprising administering to a cell extract an oligonucleotide of any one of claims 1 to 7.
- 10. A method of targeted alteration of genetic material, comprising administering to a cell an oligonucleotide of any one of claims 1 to 7.
- 11. A method of targeted alteration of genetic sequence in a subject, comprising administering to the subject an oligonucleotide of any one of claims 1 to 7.
- 12. A method of targeted alteration of genetic sequence, comprising combining target genetic material with an oligonucleotide according to any one of claims 1 to 7, said target genetic material being a non-transcribed DNA strand of a duplex DNA.
- 13. The genetic material obtained by any one of the methods of claim 8, 9 or claim 10.
- 14. A cell comprising the genetic material of claim 13.
- 15. A non-human organism comprising the cell according to claim 14.
- 16. A pharmaceutical composition comprising the oligonucleotide according to any one of claims 1 to 7.
- 17. A method of targeted chromosomal genomic alteration, comprising administering the pharmaceutical composition of claim 16 to a subject.
- 18. A non-human organism produced by the method of claim 11 or claim 17.
- 19. A method of optimizing an oligonucleotide for targeted alteration of a genetic sequence, which comprises:
(a) comparing the efficiency of alteration of a targeted genetic sequence by an oligonucleotide of any one of claims 1 to 7 with the efficiency of alteration of the same targeted genetic sequence by a second oligonucleotide, said second oligonucleotide selected from the group of (1) an oligonucleotide that is fully complementary to the target and lacks the mismatch, (2) a fully modified phosphorothiolated oligonucleotide, (3) a fully modified 2′-O-methylated oligonucleotide and (4) a chimeric double-stranded double hairpin containing RNA and DNA nucleotides.
- 20. The method of claim 19 in which the alteration is produced in a cell extract.
- 21. The method of claim 20 in which the cell extract is selected from the group of a fungal cell extract, a plant cell extract, a rodent cell extract, a primate cell extract and a human cell extract.
- 22. The method of claim 19 in which the alteration is produced in a cell.
- 23. The method of claim 21 in which the cell is selected from the group of a fungal cell, a plant cell, a rodent cell, a primate cell and a human cell.
- 24. A kit comprising the oligonucleotide according to any one of claims 1 to 7 and a second oligonucleotide selected from the group of (1) an oligonucleotide that is fully complementary to the target and lacks the mismatch, (2) a fully modified phosphorothiolated oligonucleotide, (3) a fully modified 2-O-methylated oligonucleotide and (4) a chimeric double stranded double hairpin containing RNA and DNA nucleotides.
Provisional Applications (4)
|
Number |
Date |
Country |
|
60192176 |
Mar 2000 |
US |
|
60192179 |
Mar 2000 |
US |
|
60208538 |
Jun 2000 |
US |
|
60244989 |
Oct 2000 |
US |