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.

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice

Nature Genetics volume 23, pages 471–473 (1999)Cite this article

Abstract

Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein1. The normal CAG repeat range is 5–36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats1,2,3,4,5. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion1,2,3,4,5,6. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy7,8 and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation11, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing12,13,14,15, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2–/– mice15. Our results show that Msh2 is required for somatic instability of the CAG repeat.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Typical GeneScan traces for sizing of the CAG repeat from heart and striatal tissue of Msh2–/– and Msh2+/+ mice.
Figure 2: Distribution of CAG repeats before and after the major GeneScan peak for various tissues from Msh2–/– and Msh2+/+ mice.
Figure 3: Levels of CAG repeat instability in various tissues from Msh2–/–, Msh2+/– and Msh2+/+ mice.

References

  1. Huntington 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).

  2. 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  PubMed  Google Scholar 

  3. Andrew, S.E., Goldberg, Y.P. & Hayden, M.R. Rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum. Mol. Genet. 6, 2005–2010 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Duyao, M.P. et al. Inactivation of the mouse Huntington's disease gene homolog hdh. Science 269, 407–410 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. 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  PubMed  Google Scholar 

  6. Trottier, Y., Biancalana, V. & Mandel, J.L. Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset. J. Med. Genet. 31, 377–382 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. De Rooij, K.E., De Koning Gans, P.A., Roos, R.A., Van Ommen, G.J. & Den Dunnen, J.T. Somatic expansion of the (CAG)n repeat in Huntington disease brains. Hum. Genet. 95, 270–274 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Telenius, H. et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nature Genet. 6, 409–414 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Mangiarini, L. et al. Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nature Genet. 15, 197–200 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Wheeler, V.C. et al. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum. Mol. Genet. 8, 115–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Perutz, M.F. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem. Sci. 24, 58–63 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Reitmair, A.H. et al. Mutator phenotype in Msh2-deficient murine embryonic fibroblasts. Cancer Res. 57, 3765–3771 (1997).

    CAS  PubMed  Google Scholar 

  13. Andrew, S.E. et al. Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent. Proc. Natl Acad. Sci. USA 95, 1126–1130 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baross-Francis, A., Andrew, S.E., Penney, J.E. & Jirik, F.R. Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability. Proc. Natl Acad. Sci. USA 95, 8739–8743 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Wind, N., Dekker M., Berns, A., Radman, M. & te Riele, H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Goellner, G.M. et al. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am. J. Hum. Genet. 60, 879–890 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Leeflang, E.P. et al. Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: Quantification of the mutation frequency spectrum. Hum. Mol. Genet. 4, 1519–1526 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Zuhlke, C., Riess, O., Bockel, B., Lange, H. & Thies, U. Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Hum. Mol. Genet. 2, 2063–2067 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Giovannone, B. et al. Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers. Hum. Mutat. 10, 458–464 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Manley, K., Pugh, J. & Messer, A. Instability of the CAG repeat in immortalized fibroblast cell cultures from Huntington's disease transgenic mice. Mol. Brain Res. 835, 74–79 (1999).

    Article  CAS  Google Scholar 

  22. Acharya, S. et al. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl Acad. Sci. USA 93, 13629–13634 (1996).

    Article  CAS  Google Scholar 

  23. Pearson, C.E., Ewel, A., Acharya, S., Fishel, R.A. & Sinden, R.R. Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. Hum. Mol. Genet. 6, 1117–1123 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Sugawara, N., Paques, F., Colaiacovo, M. & Haber, J.E. Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination. Proc. Natl Acad. Sci. USA 94, 9214–9219 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saparbaev, M., Prakash, L. & Prakash, S. Requirement of mismatch repair genes MSH2 and MSH3 in the RAD1-Rad10 pathway of mitotic recombination in Saccharomyces cerevisae. Genetics 142, 727–736 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Morgan, L.J. & Taylor, K.E. A polymorphic trinucleotide repeat sequence mapping to distal mouse chromosome 4. Mamm. Genome 7, 553–554 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Kim, S.J. et al. Cloning of novel trinucleotide-repeat (CAG) containing genes in mouse brain. Biochem. Biophys. Res. Commun. 240, 239–243 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H. te Riele for Msh2-deficient mice; the Wadsworth Center Molecular Genetics Core for assistance with the GeneScan analysis; S. Heverly, X. Kang, D. Pierce and K. Tartaglia for expert technical assistance; V. Bolivar for statistical assistance; and D. Nag and T. Petes for helpful discussions. This work was supported by the Hereditary Disease Foundation (Cure HD Initiative), NIH NS37299, NIH DK 52822 and the CDC National Birth Defects Study.

Author information

Authors and Affiliations

  1. New York State Department of Health, Wadsworth Center, David Axelrod Institute, Albany, New York, USA

    Kevin Manley, Thomas L. Shirley, Lorraine Flaherty & Anne Messer

  2. Department of Biomedical Sciences, The School of Public Health, SUNY Albany, Albany, New York, USA

    Thomas L. Shirley, Lorraine Flaherty & Anne Messer

Authors
  1. Kevin Manley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas L. Shirley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lorraine Flaherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Messer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Messer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Manley, K., Shirley, T., Flaherty, L. et al. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23, 471–473 (1999). https://doi.org/10.1038/70598

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/70598

This article is cited by

Search

Advanced 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