Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice

Huntington disease (HD), an autosomal dominant, progressive neurodegenerati ve disorder, is caused by an expanded CAG repeat sequence leading to an inc rease in the number of glutamine residues in the encoded protein(1). The no rmal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the numb er of CAG repeats(1-5). HD shows anticipation, in which subsequent generati ons display earlier disease onsets due to intergenerational repeat expansio n(1-6). For longer repeat lengths, somatic instability of the repeat size h as been observed both in human cases at autopsy(7,8) and in transgenic mous e models containing either a genomic fragment of human HD exon 1 (ref. 9) o r an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and become s increasingly prone to aggregation(11), suggesting important functional co rrelations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is m issing(12-15), we examined instability of the HD CAC repeat by crossing tra nsgenic mice carrying exon 1 of human HD (ref, 16) with Msh2(-/-) mice(15), Our results show that Msh2 is required for somatic instability of the CAC repeat.