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Human Molecular Genetics, 2000, Vol. 9, No. 5 779-785
© 2000 Oxford University Press

Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus

Diego Lorenzetti1,2,+, Kei Watase1,4,+, Bisong Xu1, Martin M. Matzuk1,3, Harry T. Orr5 and Huda Y. Zoghbi1,2,4,§

1Department of Molecular and Human Genetics, 2Department of Pediatrics, 3Department of Pathology and 4Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA and 5Institute for Human Genetics, University of Minnesota, Minneapolis, MN, USA

To elucidate the pathophysiology of spinocerebellar ataxia type 1 (SCA1) and to evaluate repeat length instability in the context of the mouse Sca1 gene, we generated knock-in mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion show intergenerational repeat instability (+2 to –6) at a much higher frequency in maternal transmission than in paternal transmission. The majority of changes transmitted through the female germline were small contractions, as in humans, whereas small expansions occurred more frequently in paternal transmission. The frequency of intergenerational changes was age dependent for both paternal and maternal transmissions. Mice homozygous for mutant ataxin-1 on a C57BL/6J–129/SvEv mixed background performed significantly less well on the rotating rod than did wild-type littermates at 9 months of age, although they were not ataxic by cage behavior. Histological examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathological changes observed in other transgenic models overexpressing expanded polyglutamine tracts. These data suggest that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurological phenotype reminiscent of human SCA1. Pathogenesis is thus a function of polyglutamine length, protein levels and duration of neuronal exposure to the mutant protein.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +1 713 798 6523; Fax: +1 713 798 8728; Email: hzoghbi@bcm.tmc.edu


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