Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

References

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  3. La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 352, 77–79 (1991).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Sanpei, K. 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).

    Article  CAS  Google Scholar 

  7. Imbert, G. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Zoghbi, H.Y. & Caskey, C.T. Inherited disorders caused by trinucleotide repeat expansions. Adv. Hum. Genet.(eds Harris, H. & Hirschorn, K.H. ) (Plenum, New York, in the press)

  11. Verkerk, A.J.M.H. 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).

    Article  CAS  Google Scholar 

  12. Shen, Y,, Gibbs, R.A. & Nelson, D.L. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nature Genet. 13, 109–113 (1996).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Chong, S.S. 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).

    Article  CAS  Google Scholar 

  16. Telenius, H. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Starr, T.V.B., Prystay, W. & Snutch, T.P. Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc. Natl. Acad. Sci. USA. 88, 5621–5625 (1991).

    Article  CAS  Google Scholar 

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

  22. Diriong, S., Williams, M.E., Ellis, S.B., Harpold, M.M. & Taviaux, S. Chromosomal localization of the human genes for a1A, a1B and a1E voltage-dependent Ca2+ channel subunits. Genomics. 30, 605–609 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Ophoff, R.A. 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).

    Article  CAS  Google Scholar 

  25. Llinas, R., Sugimori, M., Hillman, D.E. & Cherksey, B. Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system. Trends Neurosci. 15, 351–355 (1992).

    Article  CAS  Google Scholar 

  26. Cottingham, R.W., Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  27. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. A/at/ Acad. Sci. USA. 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  28. Subramony, S.H., Fratkin, J.D., Manyam, B.V. & Currier, R.D. 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).

    Article  CAS  Google Scholar 

  29. Stevanin, G. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Kramer, P.L. 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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  34. Elliott, M., Peroutka, S.J., Welch, S. & May, E.F. Familial hemiplegic migraine, nystagmus, and cerebellar atrophy. Annls. Neurol. 39, 1, 100–106 (1996).

    Article  CAS  Google Scholar 

  35. Koh, J.Y. & Cotman, C.W. Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonist. Brain Res. 587, 233–240 (1996).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Perez-Reyes, E., Yuan, W., Wei, X. & Bers, M. Regulation of the cloned L-type cardiac calcium channel by cyclic-AMP-dependent protein kinase FEBS Lett 342, 119–123 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Mintz, I.M., Adams, M.E. & Bean, B.P. P-type calcium channels in rat and peripheral neurons. Neuron. 9, 85–95 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Gubler, U. & Hoffman, B.J. A simple and very efficient method for generating cDNA libraries. Gene 25, 263–269 (1983).

    Article  CAS  Google Scholar 

  45. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning. A Laboratory Manual.(Cold Spring Harbor, New York, 1989)

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhuchenko, O., Bailey, J., Bonnen, P. et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nat Genet 15, 62–69 (1997). https://doi.org/10.1038/ng0197-62

Download citation

  • Received:

  • Accepted:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing