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Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation

Nature Genetics volume 15, pages 197–200 (1997)Cite this article

Abstract

Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA)1, Huntington's disease (HD)2, spinocerebellar ataxia type 1 (SCA1)3, dentatorubral pallidoluysian atrophy (DRPLA)4,5 Machado-Joseph disease (MJD or SCAB)6 and SCA27–9. Normal and expanded HD allele sizes of 6–39 and 35–121 repeats have been reported10–13, and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD14, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref. 15). Somatic repeat instability is also apparent and appears most pronounced in the CNS16,17. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested16–21. Of non-CNS tissues, instability was observed in blood, liver, kidney and colon16,20,21. A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG)45 in the androgen receptor cDNA22, (CAG)44 in the HD cDNA23, (CAG)82 in the SCA1 cDNA24, (CAG)79 in the SCA3 cDNA andas an isolated (CAG)79 tract25.

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References

  1. 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 

  2. HDCRG. A novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  3. 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 

  4. 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 

  5. 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 

  6. Kawaguchi, Y. et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8, 221–228 (1994).

    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. 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 

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

    Article  Google Scholar 

  10. Stine, O.C. et al. Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15. Hum. Mol. Genet. 2, 1547–1549 (1993).

    Article  CAS  Google Scholar 

  11. Rubinsztein, D.C. et al. Phenotypic characterisation of individuals with 30–40 CAG repeats in the Huntington's disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am. J. Hum. Genet. 59, 16–22 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Barron, L. H. et al. A study of the Huntington's disease associated trinucleotide repeat in the Scottish population. J. Med. Genet. 30, 1003–1007 (1993).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. 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 

  15. Chung, M. et al. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1. Nature Genet. 5, 254–258 (1993).

    Article  CAS  Google Scholar 

  16. Telenius, H. et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nature Genet. 6, 409–413 (1994).

    Article  CAS  Google Scholar 

  17. Ueno, S. et al. Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA). Hum. Mol. Genet. 4, 663–666 (1995).

    Article  CAS  Google Scholar 

  18. Aronin, N. et al. CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain. Neuron 15, 1193–1201 (1995).

    Article  CAS  Google Scholar 

  19. 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, 344–350 (1995).

    Article  CAS  Google Scholar 

  20. Takano, H. et al. Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability. Am. J. Hum. Genet. 58, 1212–1222 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tanaka, F. et al. Differential pattern of tissue-specific somatic mosaicism of expanded CAG trinucleotide repeat in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy. J. Neurol. Sci. 135, 43–50 (1996).

    Article  CAS  Google Scholar 

  22. Bingham, P.M. et al. Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nature Genet. 9, 191–196 (1995).

    Article  CAS  Google Scholar 

  23. Goldberg, Y.P. et al. Absence of the disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington's disease transcript. Hum. Mol. Genet. 5, 177–185 (1996).

    Article  CAS  Google Scholar 

  24. Burright, E.N. et al. SCA1 transgenic mice: a model for neurodegeration caused by an expanded CAG trinucleotide repeat. Cell 82, 937–948 (1995).

    Article  CAS  Google Scholar 

  25. Ikeda, H. et al. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Genet. 13, 196–202 (1996).

    Article  CAS  Google Scholar 

  26. Mangiarini, L. et al. Exon 1 of the Huntington's disease gene containing a highly expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 497–506 (1996).

    Article  Google Scholar 

  27. Krawczak, M. et al. Covariate-dependent age-at-onset distributions for Huntington's disease. Am. J. Hum. Genet. 49, 735–745 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Farrer, L.A., Cupples, L.A., Kiely, D.K., Conneally, P.M. .& Myers, R.H. Inverse relationship between age at onset of Huntington's disease and paternal age suggests involvement of genetic imprinting. Am. J. Hum. Genet. 50, 528–535 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the mouse embryo, a laboratory manual. (Cold Spring Harbor Press, New York, 1994).

  30. Riess, O., Noerremoelle, A., Soerensen, S.A. & Epplen, J.T. Improved PCR conditions for the stretch of (CAG)n repeats causing Huntington's disease. Hum. Mol. Genet. 2, 637 (1993).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Medical and Molecular Genetics, 8th Floor, Guy's Tower, Guy's Hospital, London, SEl 9RT, UK

    Laura Mangiarini, Kirupa Sathasivam, Amarbirpal Mahal, Mary Seller & Gillian P. Bates

  2. Sanger Centre, Hinxton Hall, Hinxton, Cambs, CB1O 1RO, UK

    Richard Mott

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Correspondence to Gillian P. Bates.

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Mangiarini, L., Sathasivam, K., Mahal, A. et al. Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet 15, 197–200 (1997). https://doi.org/10.1038/ng0297-197

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