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Human Molecular Genetics, 2003, Vol. 12, No. 1 41-50
© 2003 Oxford University Press

Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice

Randell T. Libby1, Darren G. Monckton5, Ying-Hui Fu6, Refugio A. Martinez1, John P. McAbney5, R. Lau7, David D. Einum8, K. Nichol7, Carol B. Ware2, Louis J. Ptacek8,9, Christopher E. Pearson7 and Albert R. La Spada1,3,4,*

1Department of Laboratory Medicine, 2Department of Comparative Medicine, 3Department of Medicine (Division of Medical Genetics) and 4Department of Neurology, University of Washington Medical Center, Seattle, WA, USA, 5Institute for Biomedical and Life Sciences, University of Glasgow, Glasgow, UK, 6Department of Human Genetics, University of California (San Francisco), San Francisco, CA, USA, 7Department of Genetics, Hospital for Sick Children, Toronto, Ontario, Canada and 8Department of Human Genetics and 9Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA

Received August 19, 2002; Accepted November 2, 2002

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in the ataxin-7 gene. In humans, SCA7 is characterized by marked anticipation due to intergenerational repeat instability with a bias toward expansion, and is thus regarded as the most unstable of the polyglutamine diseases. To study the molecular basis of CAG/CTG repeat instability and its pathological significance, we generated lines of transgenic mice carrying either a SCA7 cDNA construct or a 13.5 kb SCA7 genomic fragment with 92 CAG repeats. While the cDNA transgenic mice showed little intergenerational repeat instability, the genomic fragment transgenic mice displayed marked intergenerational instability with an obvious expansion bias. We then went on to generate additional lines of genomic fragment transgenic mice, and observed that deletion of the 3' genomic region significantly stabilized intergenerational transmission of the SCA7 CAG92 repeat. These results suggest that cis-information present on the genomic fragment is driving the instability process. As the SCA7 genomic fragment contains a large number of replication-associated motifs, the presence of such sequence elements may make the SCA7 CAG repeat region more susceptible to instability. Small-pool and standard PCR analysis of tissues from genomic fragment mice revealed large repeat expansions in their brains and livers, but no such changes were found in any tissues from cDNA transgenic mice that have been shown to undergo neurodegeneration. As large somatic repeat expansions are absent from the brains of SCA7 cDNA mice, our results indicate that neurodegeneration can occur without marked somatic mosaicism, at least in these mice.

* To whom correspondence should be addressed at: Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA 98195-7110, USA. Tel: +1 2065982138; Fax: +1 2065986189; Email: laspada{at}u.washington.edu


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