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 exhibit strikin g length-dependent intergenerational instability, typically small size incr eases or decreases of one to a few CAGs, but little variation in somatic ti ssues. In a subset of male transmissions, larger size increases occur to pr oduce extreme HD alleles that display somatic instability and cause juvenil e onset of the disorder. Initial efforts to reproduce these features in a m ouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability (similar to 2% of meioses), A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh ge ne. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being m ore evident in female transmissions. No large jumps in CAG length were dete cted in either male or female transmissions. Instead, size changes were mod est increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissue s gave way to marked mosaicism in liver and striatum for the longest repeat s in older mice. These results indicate that gametogenesis is the primary s ource of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreove r, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a differen t fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.