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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.

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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.

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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.

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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

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  1. Kevin Manley
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Correspondence to Anne Messer.

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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

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