Human Molecular Genetics, 2000, Vol. 9, No. 18 2767-2775
© 2000 Oxford University Press
Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington’s disease gene
1Departments of Molecular Pharmacology and Experimental Therapeutics, 2Health Sciences Research, Section of Biostatistics, 3Biochemistry and Molecular Biology and 4Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, MN 55905, USA
Gender is known to influence the transmission of trinucleotide repeats in human disease. However, the molecular basis for the parent-of-origin effect associated with trinucleotide repeat expansion is not known. We have followed, during transmission, the fate of the CAG trinucleotide repeat in a transgene containing the exon 1 portion of the human Huntington’s disease (HD) gene. Similar to humans, the mouse transmits expansions predominantly through the male germ line. Surprisingly, we find that the CAG repeat size of the mutant human HD gene is different in male and female progeny from identical fathers. Males predominantly expand the repeat whereas females predominantly contract the repeat. In contrast to the classic definition of imprinting, CAG expansion is influenced by the gender of the embryo. Our results raise the possibility that there are X- or Y-encoded factors that influence repair or replication of DNA in the embryo. Gender dependence in the embryo may explain why expansion in HD from premutation to disease primarily occurs through the paternal line.
+ To whom correspondence should be addressed. Tel: +1 507 284 1597; Fax: +1 507 284 9111; Email: mcmurray.cynthia@mayo.edu
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