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Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the  HTT  CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes,  FAN1  and  RRM2B,  for an influence on somatic instability of the expanded CAG repeat in  Htt  CAG knock-in mice.  Fan1  knock-out increased somatic expansion of  Htt  CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of  Rrm2b  did not greatly alter somatic  Htt  CAG repeat instability. Simultaneous knock-out of  Mlh1 , the ortholog of a third HD age-at-onset modifier gene ( MLH1 ), which suppresses somatic expansion of the  Htt  knock-in CAG repeat, blocked the  Fan1  knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the  RRM2B  modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the  FAN1  modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out