C013 The role of FAN1 in mouse models of Huntington’s disease

<h3>Background</h3> Age at motor onset (AMO) of Huntington’s disease (HD) is inversely correlated with the length of the inherited HTT CAG repeat tract but is strongly influenced by genetic modifiers. Genome-wide association studies (GWAS) have consistently implicated genetic variation at DNA repair gene loci in modification of HD AMO. Variation at these loci is thought to modify AMO by either promoting or suppressing somatic expansion in vulnerable tissues. Several AMO-modifying single nucleotide polymorphisms (SNPs) have been identified at the FAN1 locus. Furthermore, experimental evidence from HD and other trinucleotide repeat disease models has suggested a protective role of FAN1 in limiting somatic expansion. <h3>Aims</h3> We aimed to investigate whether Fan1 knockout (KO) or disruption of FAN1 protein function affected the extent of somatic expansion and/or AMO in HD mice. <h3>Methods/Techniques</h3> We bred R6/1 mice with Fan1 KO, Fan1 p.R510H and Fan1 p.D963A mutant mice. Animals underwent longitudinal motor testing, and the extent of tissue-specific somatic expansion was measured by capillary electrophoresis. <h3>Results/Outcome</h3> R6/1 x Fan1-/- mice displayed increased tissue-specific somatic expansion in the striatum, liver, and tail at 26-weeks of age while R6/1 x Fan1+/- mice did not differ from R6/1 x Fan1+/+ controls. We detected no overt difference in motor coordination between genotypes from 12 to 24 weeks of age. <h3>Conclusions</h3> FAN1 has a tissue-specific role in limiting somatic expansion, including in the striatum, but its loss does not appear to significantly alter motor coordination in R6/1 mice.