Human Molecular Genetics, Vol 5, 177-185, Copyright © 1996 by Oxford University Press
YP Goldberg, MA Kalchman, M Metzler, J Nasir, J Zeisler, R Graham, HB Koide, J O'Kusky, AH Sharp, CA Ross, F Jirik and MR Hayden
The mutation underlying Huntington disease (HD) is CAG expansion in the
first exon of the HD gene. In order to investigate the role of CAG
expansion in the pathogenesis of HD, we have produced transgenic mice
containing the full length human HD cDNA with 44 CAG repeats. By 1 year,
these mice have no behavioral abnormalities and morphometric analysis at 6
(one animal) and 9 (two animals) months age revealed no changes. Despite
high levels of mRNA expression, there was no evidence of the HD gene
product in any of these transgenic mice. In vitro transfection studies
indicated that the inclusion of 120 bp of the 5' UTR in the cDNA construct
and the presence of a frameshift mutation at nucleotide 2349 prevented
expression of the HD cDNA. These findings suggest that the pathogenesis of
HD is not mediated through DNA-protein interaction and that presence of the
RNA transcript with an expanded CAG repeat is insufficient to cause the
disease. Rather, translation of the CAG is crucial for the pathogenesis of
HD. In contrast to that seen in humans, the CAG repeat in these mice was
remarkably stable in 97 meioses. This suggests that genomic sequences may
play a critical role in influencing repeat instability.
ARTICLES
Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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