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Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel

Nature Genetics volume 15, pages 6269 (1997) | Download Citation

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Abstract

A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.

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References

  1. 1.

    The expanding world of trinucleotide repeats. Science. 271, 1374–1375 (1996).

  2. 2.

    Huntington's disease collaborative research group A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 72, 971–983 (1993).

  3. 3.

    , , , & Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 352, 77–79 (1991).

  4. 4.

    et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellarataxiatype. Nature Genet. 4, 221–226 (1993).

  5. 5.

    et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nature Genet. . 14, 269–276 (1996).

  6. 6.

    et al. Identification of the gene for spinocerebellar ataxia type 2 using a direct identification of repeat expansion and cloning technique, DIRECT. Nature Genet. 14, 277–284 (1996).

  7. 7.

    et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nature Genet. 14, 285–291 (1996).

  8. 8.

    et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8, 221–235 (1994).

  9. 9.

    et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet. 6, 9–13 (1994).

  10. 10.

    & Inherited disorders caused by trinucleotide repeat expansions. Adv. Hum. Genet.(eds & ) (Plenum, New York, in the press)

  11. 11.

    et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 65, 905–914 (1991).

  12. 12.

    , & Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nature Genet. 13, 109–113 (1996).

  13. 13.

    et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1259 (1992).

  14. 14.

    et al. Friedreich's ataxia: autosomal recessive disease caused by an intronicGAA triplet repeat expansion. Science 271, 1423–1427 (1996).

  15. 15.

    et al. Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 10, 344–353 (1995).

  16. 16.

    et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum. Mol. Genet. 2, 1535–1540 (1993).

  17. 17.

    Gain of glutamines, gain of function. Nature Genet. 10, 3–4 (1995).

  18. 18.

    et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature. 378, 403–406 (1995).

  19. 19.

    et al. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature. 350, 398–402 (1991).

  20. 20.

    , & Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc. Natl. Acad. Sci. USA. 88, 5621–5625 (1991).

  21. 21.

    et al. Isoform-specific interaction of the. Natl. Acad. Sci. USA 93, 7363–7368 (1996).

  22. 22.

    , , , & Chromosomal localization of the human genes for a1A, a1B and a1E voltage-dependent Ca2+ channel subunits. Genomics. 30, 605–609 (1995).

  23. 23.

    Margolis et al.Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. Somat. Cell Mol. Genet 21, 279–284 (1995).

  24. 24.

    et al. Familial hemiplegic migraine and episodic ataxia type 2 are cause by mutations in the Ca2+ channel gene CACNL1A4. Cell,. 87, 543–552 (1996).

  25. 25.

    , , & Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system. Trends Neurosci. 15, 351–355 (1992).

  26. 26.

    , & Faster sequential genetic linkage computations. Am. J. Hum. Genet 53, 252–263 (1993).

  27. 27.

    , , & Strategies for multilocus linkage analysis in humans. Proc. A/at/ Acad. Sci. USA. 81, 3443–3446 (1984).

  28. 28.

    , , & Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-l, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian Atrophy locus. Movement Disorders. 11, 174–180 (1996).

  29. 29.

    et al. A third locus for autosomal dominant cerebellar ataxia type 1 maps to chromosome 14q24.3-qter evidence for the existence of a fourth locus. Am. J. Hum. Genet. 54, 11–20 (1994).

  30. 30.

    et al. Autosomal dominant cerebellar ataxia with dementia: evidence of a fourth disease locus. Hum. Mol. Genet. 1, 177–190 (1994).

  31. 31.

    et al. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. /\nn/s. A/euro/. 37, 289–293 (1995).

  32. 32.

    et al. A locus for the nystagmus-associated form of episodic ataxia maps to an 11-cM region on chromosome 19p. Am. J. Hum. Genet. 57, 182–185 (1995).

  33. 33.

    et al. A gene for familial hemiplegic migraine maps to chromosome 19. Nature Genet. 5, 41–45 (1993).

  34. 34.

    , , & Familial hemiplegic migraine, nystagmus, and cerebellar atrophy. Annls. Neurol. 39, 1, 100–106 (1996).

  35. 35.

    & Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonist. Brain Res. 587, 233–240 (1996).

  36. 36.

    Structure and function of voltage-gated ion channels. Annu. Rev. Biochem. 64, 493–531 (1995).

  37. 37.

    , , & Regulation of the cloned L-type cardiac calcium channel by cyclic-AMP-dependent protein kinase FEBS Lett 342, 119–123 (1994).

  38. 38.

    et al. Localization and functional properties of a rat brain Natl. Acad. Sci. USA 91, 10576–10580 (1994).

  39. 39.

    Let al. The naming of voltage-gated calcium channels. Neuron. 13, 505–506 (1994).

  40. 40.

    et al. Distinctive pharmacology and kinetics of cloned neuronal Ca2* channels and their possible counterparts in mammalian CNS neurons. Neuropharmacology. 32, 1075–1088 (1993).

  41. 41.

    , & P-type calcium channels in rat and peripheral neurons. Neuron. 9, 85–95 (1992).

  42. 42.

    et al. Absence epilepsy in Tottering mutant mice is associated with calcium channel defects. Cell. 87, 607–617 (1996).

  43. 43.

    Block of Ca channels in rat central neurons by the spider toxin omega-Aga-IIIA 7. Neurosci. 14, 2844–2853 (1994).

  44. 44.

    & A simple and very efficient method for generating cDNA libraries. Gene 25, 263–269 (1983).

  45. 45.

    , & Molecular Cloning. A Laboratory Manual.(Cold Spring Harbor, New York, 1989)

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Affiliations

  1. Departments of Molecular and Human Genetics Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

    • Olga Zhuchenko
    • , Jennifer Bailey
    • , Penelope Bonnen
    • , David W. Stockton
    • , Huda Y. Zoghbi
    •  & Cheng Chi Lee
  2. Departments of Neurology and the Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

    • Tetsuo Ashizawa
    •  & Huda Y. Zoghbi
  3. Veterans Affairs Medical Center and Houston, Texas 77030, USA.

    • Tetsuo Ashizawa
  4. UTMD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Chris Amos
  5. Department of Neurology and Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.

    • William B. Dobyns
  6. University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. Correspondence should be addressed to C.C.I.

    • S.H. Subramony
  7. Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

    • Huda Y. Zoghbi
  8. All correspondence should be addressed to C.C.L.

    • Cheng Chi Lee

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DOI

https://doi.org/10.1038/ng0197-62

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