Claims
- 1. An isolated polypeptide selected from the group consisting of:
a) a polypeptide comprising SEQ ID NO: 49; b) a polypeptide comprising SEQ ID NO: 51; c) a polypeptide comprising SEQ ID NO: 53; d) a polypeptide comprising SEQ ID NO: 55; e) a polypeptide comprising SEQ ID NO: 57; f) a polypeptide comprising SEQ ID NO: 61; g) a polypeptide comprising SEQ ID NO: 63; h) a polypeptide comprising amino acids 25 to 47 of SEQ ID NO: 51; i) a mutein of any of (a) to (h), wherein the amino acid sequence has at least 60% or 70% or 80% or 90% or 95% or 99% identity to at least one of the sequences in (a) to (h); j) a mutein of any of (a) to (h) which is encoded by a DNA sequence which hybridizes to the complement of the DNA sequence encoding any of (a) to (h) under moderately stringent conditions or under highly stringent conditions; and k) a mutein of any of (a) to (h) wherein any changes in the amino acid sequence are conservative amino acid substitutions to the amino acid sequences in (a) to (h).
- 2. The polypeptide of claim 1, wherein said polypeptide is capable of binding a KCNQ2 polypeptide comprising exon 15b shown at position 545 to 643 of SEQ ID NO: 2.
- 3. The polypeptide of claim 1 or 2, wherein said polypeptide is capable of binding a catalytic subunit or a scaffolding subunit of a PP2A phosphatase.
- 4. A purified polynucleotide encoding the polypeptide of any of claims 1 to 3, or a polynucleotide complementary thereto.
- 5. The polynucleotide of claim 4, wherein said polynucleotide is selected from the group consisting of:
a) a polynucleotide comprising SEQ ID NO: 48; b) a polynucleotide comprising SEQ ID NO: 50; c) a polynucleotide comprising SEQ ID NO: 52; d) a polynucleotide comprising SEQ ID NO: 54; e) a polynucleotide comprising SEQ ID NO: 56; f) a polynucleotide comprising SEQ ID NO: 58; g) a polynucleotide comprising SEQ ID NO: 60; h) a polynucleotide comprising SEQ ID NO: 62; i) a polynucleotide complementary to any of the polynucleotides of (a) to (h); and j) a polynucleotide hybridizing to any of the polynucleotides of (a) to (h) under moderately stringent conditions or under highly stringent conditions.
- 6. An expression vector comprising the polynucleotide of claims 4 or 5.
- 7. The expression vector of claim 6, wherein said vector is a gene therapy vector.
- 8. A host cell comprising the expression vector of claims 6 or 7.
- 9. A method of making a polypeptide, said method comprising the steps of culturing a host cell according to claim 8 under conditions suitable for the production of a polypeptide of any of claims 1 to 3 within said host cell.
- 10. The method of claim 9, further comprising the step of purifying said polypeptide from the culture.
- 11. An antibody that specifically binds to a polypeptide of any of claims 1 to 3.
- 12. Use of a PP2A/Bγ subunit as a target for screening candidate modulators.
- 13. Use of a PP2A phosphatase comprising a PP2A/Bγ subunit as a target for screening candidate modulators.
- 14. The use of claims 12 or 13, wherein said modulator specifically modulates a PP2A phosphatase comprising said PP2A/Bγ subunit.
- 15. The use of any of claims 12 to 14, wherein said candidate modulator is selected from the group consisting of a natural ligand, a small molecule, an antibody, an antisense RNA, an aptamer and a short interfering RNA.
- 16. The use of any of claims 12 to 15, wherein said modulator is a candidate drug for the treatment of a mental disorder.
- 17. Use of modulator of a PP2A phosphatase comprising a PP2A/Bγ subunit for preparing a medicament for the treatment of a mental disorder.
- 18. The use of claim 17, wherein said modulator specifically modulates a PP2A phosphatase comprising said PP2A/Bγ subunit.
- 19. Use of a gene therapy vector comprising a polynucleotide encoding a PP2A/Bγ subunit for preparing a medicament for the treatment of a mental disorder.
- 20. The use of any of claims 12 to 19, wherein said modulator is used in combination with a known drug for said treatment of said mental disorder.
- 21. The use of any of claims 16 to 20, wherein said mental disorder is selected from the group consisting of bipolar disorder, schizophrenia and depression.
- 22. The use of claim 21, wherein said mental disorder is bipolar disorder.
- 23. Use of a PP2A/Bγ subunit as a target for screening for natural binding partners.
- 24. The use of any of claims 12 to 23, wherein said PP2A/Bγ subunit is a polypeptide of SEQ ID NO: 38.
- 25. The use of any of claims 12 to 23, wherein said PP2A/Bγ subunit is the polypeptide of any of claims 1 to 3.
- 26. A method of assessing the efficiency of a modulator of a PP2A phosphatase comprising a PP2A/Bγ subunit for the treatment of a mental disorder, said method comprising administering said modulator to an animal model for said mental disorder; wherein a determination that said modulator ameliorates a representative characteristic of said mental disorder in said animal model indicates that said agonist is a drug for the treatment of said mental disorder.
- 27. The method of claim 26, wherein said animal model is the STOP−/− mice with synaptic defects and severe behavioral disorders.
- 28. The method of claims 26 or 27, wherein said modulator specifically modulates a PP2A phosphatase comprising the PP2A/Bγ subunit.
- 29. The method of any of claims 26 to 28, wherein said mental disorder is selected from the group consisting of bipolar disorder, schizophrenia and depression.
- 30. The method of claim 29, wherein said mental disorder is bipolar disorder.
- 31. The method of any of 26 to 30, wherein said PP2A/Bγ subunit is a polypeptide of SEQ ID NO: 38.
- 32. The method of any of 26 to 30, wherein said PP2A/Bγ subunit is a polypeptide of any of claims 1 to 3.
- 33. Use of at least one PP2A/Bγ-related biallelic marker for diagnosing whether an individual suffers from or is at risk of suffering from a mental disorder.
- 34. The use of claim 33, wherein said PP2A/Bγ-related biallelic marker is selected from the group consisting of 99-24169/139, 24-257/320, 99-24175/218 and 24-247/216 as depicted in table 3A and the complements thereof.
- 35. The use of claim 34, wherein presence of a genotype “AA” at biallelic marker 99-24169/139 is indicative of said individual suffering from or being at risk of suffering from said mental disorder.
- 36. The use of claim 34, wherein the presence a haplotype “AG” at biallelic markers 24169/139 and 24-247/216 is indicative of said individual suffering from or being at risk of suffering from said mental disorder.
- 37. The use of claim 34, wherein presence of a haplotype “AA” at biallelic markers 24-257/320 and 99-24175/218 is indicative of said individual suffering from or being at risk of suffering from said mental disorder.
- 38. Use of at least one PP2A/Bγ-related biallelic marker for determining whether there is a significant association between said marker and a mental disorder.
- 39. The use of claim 38, wherein said PP2A/Bγ-related biallelic marker is selected from the group consisting of 99-24169/139, 24-257/320, 99-24175/218 and 24-247/216 as depicted in table 3A and the complements thereof.
- 40. The use of any of claims 33 to 39, wherein said mental disorder is selected from the group consisting of bipolar disorder, schizophrenia and depression.
- 41. The use of claim 40, wherein said mental disorder is bipolar disorder.
- 42. A method of genotyping comprising the step of determining the identity of a nucleotide at a PP2A/Bγ-related biallelic marker or the complement thereof in a biological sample.
- 43. The method of claim 42, wherein said biological sample is derived from a single subject.
- 44. The method of claim 43, wherein the identity of the nucleotides at said biallelic marker is determined for both copies of said biallelic marker present in said individual's genome.
- 45. The method of any of claims 42 to 44, wherein said determining is performed by a microsequencing assay.
- 46. The method of any of claims 42 to 45, further comprising amplifying a portion of said sequence comprising the biallelic marker prior to said determining step.
- 47. The method of claim 46, wherein said amplifying is performed by PCR.
- 48. A method of diagnosing a mental disorder in an individual comprising the step of genotyping at least one PP2A/Bγ-related biallelic marker according to the method of any of claims 43 to 47.
- 49. The method of claim 48 further comprising the step of correlating the result of the genotyping step with a risk of suffering from said mental disorder.
- 50. The method of claim 48 or 49, wherein said PP2A/Bγ-related biallelic marker is selected from the group consisting of 99-24169/139, 24-257/320, 99-24175/218 and 24-247/216 as depicted in table 3A and the complements thereof.
- 51. The method of claim 50, wherein presence of a genotype “AA” at biallelic marker 99-24169/139 is indicative of a risk of suffering from said mental disorder.
- 52. The method of claim 50, wherein the presence a haplotype “AG” at biallelic markers 24169/139 and 24-247/216 is indicative of a risk of suffering from said mental disorder.
- 53. The method of claim 50, wherein presence of a haplotype “AA” at biallelic markers 24-257/320 and 99-24175/218 is indicative of a risk of suffering from said mental disorder.
- 54. The method of any of claims 48 to 53, wherein said mental disorder is selected from the group consisting of bipolar disorder, schizophrenia and depression.
- 55. The method of claim 54, wherein said mental disorder is bipolar disorder.
- 56. Use of a polynucleotide comprising a contiguous span of at least 12 nucleotides of SEQ ID NO: 37 or a polynucleotide complementary thereto in a microsequencing assay for determining the identity of the nucleotide at a PP2A/Bγ-related biallelic marker, wherein the 3′ end of said polynucleotide is located 1 nucleotide upstream of said PP2A/Bγ-related biallelic marker in said sequence.
- 57. The use of claim 56, wherein said at least one PP2A/Bγ-related biallelic marker is selected from the group consisting of 99-24169/139, 24-257/320, 99-24175/218 and 24-247/216 as depicted in table 3A and the complements thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of PCT/EP03/50247, filed Jun. 20, 2003, which claims the benefit of U.S. Provisional 60/391,359, filed Jun. 25, 2002. Each of these applications is hereby incorporated by reference in their entireties, including all figures, tables, formulae, amino acid sequences, and nucleic acid sequences.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60391359 |
Jun 2002 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
PCT/EP03/50247 |
Jun 2003 |
US |
Child |
10744796 |
Dec 2003 |
US |