Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse

The CAG repeats in the human Huntington's disease (HD) gene exhibitstriking length-dependent intergenerational instability, typically smallsize increases or decreases of one to a few CAGs, but little variation insomatic tissues. In a subset of male transmissions, larger size increasesoccur to produce extreme HD alleles that display somatic instability andcause juvenile onset of the disorder. Initial efforts to reproduce thesefeatures in a mouse model transgenic for HD exon 1 with 48 CAG repeatsrevealed only mild intergenerational instability ( approximately 2% ofmeioses). A similar pattern was obtained when this repeat was inserted intoexon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90and 109 units produced a graded increase in the mutation frequency to>70%, with instability being more evident in female transmissions. Nolarge jumps in CAG length were detected in either male or femaletransmissions. Instead, size changes were modest increases and decreases,with expansions typically emanating from males and contractions fromfemales. Limited CAG variation in the somatic tissues gave way to markedmosaicism in liver and striatum for the longest repeats in older mice.These results indicate that gametogenesis is the primary source ofinherited instability in the Hdh knock-in mouse, as it is in man, but thatthe underlying repeat length-dependent mechanism, which may or may not berelated in the two species, operates at higher CAG numbers. Moreover, thelarge CAG repeat increases seen in a subset of male HD transmissions arenot reproduced in the mouse, suggesting that these arise by a differentfundamental mechanism than the small size fluctuations that are frequentduring gametogenesis in both species.