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CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1

Nature Genetics volume 8, pages 221–228 (1994)Cite this article

Abstract

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68–79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

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References

  1. Isselbacher, K.J. et al. in Harrison's Principles of Internal Medicine 13th edn (McGraw-Hill, New York, 1994).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Brook, J.D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

    Article  CAS  Google Scholar 

  4. Harley, H.G. et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355, 545–546 (1992).

    Article  CAS  Google Scholar 

  5. Buxton, J. et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 355, 547–548 (1992).

    Article  CAS  Google Scholar 

  6. Aslanidis, C. et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355, 548–551 (1992).

    Article  CAS  Google Scholar 

  7. Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

    Article  CAS  Google Scholar 

  8. Fu, Y.-H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).

    Article  CAS  Google Scholar 

  9. The 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 

  10. Orr, H.T. et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221–226 (1993).

    Article  CAS  Google Scholar 

  11. 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 

  12. Nagafuchi, S. et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet. 6, 14–18 (1994).

    Article  CAS  Google Scholar 

  13. Fu, Y.-H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

    Article  CAS  Google Scholar 

  14. Knight, S.J.L. et al. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74, 127–134 (1993).

    Article  CAS  Google Scholar 

  15. Duyao, M. et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genet. 4, 387–392 (1993).

    Article  CAS  Google Scholar 

  16. Snell, R.G. et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genet. 4, 393–397 (1993).

    Article  CAS  Google Scholar 

  17. Andrew, S.E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet. 4, 398–403 (1993).

    Article  CAS  Google Scholar 

  18. Gispert, S. et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1. Nature Genet. 4, 295–299 (1993).

    Article  CAS  Google Scholar 

  19. Nakano, K.K., Dawson, D.M. & Spence, A. Machado disease. A hereditary ataxia in Portuguse emigrants to Massachusetts. Neurology 22, 49–55 (1972).

    Article  CAS  Google Scholar 

  20. Lima, L. & Coutinho, P. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorean Portuguese family. Neurology 30, 319–322 (1980).

    Article  CAS  Google Scholar 

  21. Healton, E.B., Brust, J.C.M., Kerr, D.L., Resor, S. & Penn, A. Presumbly Azorean disease in a presumably non-Portuguese family. Neurology 30, 1084–1089 (1980).

    Article  CAS  Google Scholar 

  22. Sakai, T., Ohta, M. & Ishino, H. Joseph disease in a non-Portuguese family. Neurology 33, 74–80 (1983).

    Article  CAS  Google Scholar 

  23. Bharucha, N.E., Bharucha, E.P. & Bhabha, S.K. Machado-Joseph-Azorean disease in India. Arch. Neurol. 43, 142–144 (1986).

    Article  CAS  Google Scholar 

  24. Suite, N.D.A., Sequeiros, J. & Mckhan, G.M. Machado-Joseph disease in a Sicilian-American family. J. Neurogenet. 3, 177–182 (1986).

    Article  CAS  Google Scholar 

  25. Barbeau, A. et al. The natural history of Machado-Joseph disease. An analysis of 138 personally examined cases. Can. J. neurol. Sci. 11, 510–525 (1984).

    Article  CAS  Google Scholar 

  26. Rosenberg, R.N. Machado-Joseph disease: An autosomal dominant system degeneration. Mov. Dis. 3, 193–203 (1992).

    Article  Google Scholar 

  27. Takiyama, Y. et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nature Genet. 4, 300–304 (1993).

    Article  CAS  Google Scholar 

  28. Hyslop, P.S.G. et al. Machado-Joseph disease in pedigrees of Azorean descent is linked to chromosome 14. Am. J. hum. Genet. 55, 120–125 (1994).

    Google Scholar 

  29. Krainer, A.R. & Maniatis, T. RNA splicing. in Transcription and splicing (eds Hames, B.D.& Glover, D.M.) 131–206 (IRL press, Oxford, 1988).

    Google Scholar 

  30. Strong, T.V. et al. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nature Genet. 5, 259–265 (1993).

    Article  CAS  Google Scholar 

  31. Karp, S.J., Masu, M., Eki, T., Ozawa, K. & Nakanishi, S. Molecular cloning and chromosomal localization of the key subunit of the human N-Methyl-D-aspartate receptor. J. biol. Chem. 268, 3728–3733 (1993).

    CAS  PubMed  Google Scholar 

  32. Kakizuka, A. et al. A mouse cdc25 homologue is differentially and developmentally expressed. Genes Devel. 6, 578–590 (1992).

    Article  CAS  Google Scholar 

  33. Maniatis, T., Fritsch, E.F. & Shambrook, J. in Molecular Cloning: a Laboratory Manual2nd edn (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  34. Taniwaki, M. et al. Detection of 14q32 translations in B-cell malignancies by in situ hybridization with yeast artificial chromosome clones containing the human IgH gene locus. Blood 83, 2962–2969 (1994).

    CAS  PubMed  Google Scholar 

  35. Taniwaki, M. et al. Characterization of two marker chromosomes in a patient with acute nonlymphocytic leukemia by two-color fluorescence in situ hybridization. Cancer Genet. Cytogenet. 70, 99–102 (1993).

    Article  CAS  Google Scholar 

  36. Matsuda, F. et al. Structure and physical map of 64 variable segments in the 3′ 0.8-megabase region of the human immunoglobulin heavy-chain locus. Nature Genet. 3, 88–94 (1993).

    Article  CAS  Google Scholar 

  37. Vandenplas, S. et al. Blot hybridisation analysis of genomic DNA. J. med. Genet. 21, 164–172 (1984).

    Article  CAS  Google Scholar 

  38. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  Google Scholar 

  39. Inoue, J., Kerr, L.D., Kakizuka, A. & Verma, I.M. IκEγ, a70 kd protein identical to the C-terminal half of p110 NF-κB: a new member of the IκB family. Cell 68, 1109–1120 (1992).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, 606-01, Japan

    Yoshiya Kawaguchi, Toshihiro Okamoto, Megumi Aizawa, Miho Inoue, Shuh Narumiya & Akira Kakizuka

  2. The 3rd Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602, Japan

    Masafumi Taniwaki

  3. The 3rd Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, 734, Japan

    Sadao Katayama, Hideshi Kawakami & Shigenobu Nakamura

  4. Department of Neurology, Kyoto University Faculty of Medicine, Kyoto, 606-01, Japan

    Masaki Nishimura, Ichiro Akiguchi & Jun Kimura

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Kawaguchi, Y., Okamoto, T., Taniwaki, M. et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8, 221–228 (1994). https://doi.org/10.1038/ng1194-221

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