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Human Molecular Genetics Advance Access published online on September 2, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg300
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1

Kei Watase 1, Koen J.T. Venken 2, Yaling Sun 3, Harry T. Orr 4, and Huda Y. Zoghbi 5*

1 Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
2 Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
3 Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
4 Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA
5 Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

* To whom correspondence should be addressed. E-mail: hzoghbi{at}bcm.tmc.edu.


  Abstract

Expression of unstable translated CAG repeats is the mutational mechanism in nine different neurodegenerative disorders. Although the products of genes harboring these repeats are widely expressed, a subset of neurons is vulnerable in each disease accounting for the different phenotypes. Somatic instability of the expanded CAG repeat has been implicated as a factor mediating the selective striatal neurodegeneration in Huntington disease. It remains unknown, however, whether such a mechanism contributes to the selective neurodegeneration in other polyglutamine diseases or not. To address this question, we investigated the pattern of CAG repeat instability in a knock-in mouse model of spinocerebellar ataxia type 1 (SCA1). Small pool PCR analysis on DNA from various neuronal and nonneuronal tissues revealed that somatic repeat instability was most remarkable in the striatum. In the two vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profiles of mosaicism. These results suggest that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knock-in models of polyglutamine diseases highlights the role of trans-acting tissue- or cell-specific factors in mediating the instability.


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