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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3359-3367
DOI: 10.1093/hmg/ddg352
© 2003 Oxford University Press

Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis

Laura Kennedy1, Elizabeth Evans1, Chiung-Mei Chen1, Lyndsey Craven1, Peter J. Detloff2, Margaret Ennis1 and Peggy F. Shelbourne1,*

1Division of Molecular Genetics, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK and 2Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 720 20th Street South, Birmingham, Alabama, USA

Received August 26, 2003; Revised September 29, 2003; Accepted October 13, 2003

Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.

* To whom correspondence should be addressed at: Division of Molecular Genetics, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK. Tel: +44 1413306200; Fax: +44 01413306871; Email: ps17z{at}udcf.gla.ac.uk


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