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Human Molecular Genetics, Vol 8, 763-774, Copyright © 1999 by Oxford University Press

ARTICLES

A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice

PF Shelbourne, N Killeen, RF Hevner, HM Johnston, L Tecott, M Lewandoski, M Ennis, L Ramirez, Z Li, C Iannicola, DR Littman and RM Myers
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. ps7z@udcf.gla.ac.uk

Huntington's disease (HD) is a dominant disorder characterized by premature and progressive neurodegeneration. In order to generate an accurate model of the disease, we introduced an HD-like mutation (an extended stretch of 72-80 CAG repeats) into the endogenous mouse Hdh gene. Analysis of the mutation in vivo reveals significant levels of germline instability, with expansions, contractions and sex-of-origin effects in evidence. Mice expressing full-length mutant protein display abnormal social behaviour in the absence of acute neurodegeneration. Given that psychiatric changes, including irritability and aggression, are common findings in HD patients, our data are consistent with the hypothesis that some clinical features of HD may be caused by pathological processes that precede gross neuronal cell death. This implies that effective treatment of HD may require an understanding and amelioration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain. These mice should facilitate the investigation of the molecular mechanisms that underpin the pathway from genotype to phenotype in HD.
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