Figure 1.

MLH3 endonuclease domain mutation eliminates HTT CAG expansion in Htt^Q111 mice. (A) Schematic representation of MLH3 protein and its functional domains, as well as mutation of the endonucleolytic motif in Mlh3^DN mice (adapted from Toledo et al. (42)). (B) Quantification of HTT CAG expansions in striatum, liver, and kidney at 3 and 6 months (M) of age in Htt^Q111 knock-in mice that are either wild type (Mlh3^WT/WT, 3M CAG 115–122, 6M CAG 114–121), heterozygous (Mlh3^WT/DN, 3M CAG 115–121, 6M CAG 116–121), or homozygous (Mlh3^DN/DN, 3M CAG 116–121, 6M CAG 116–121) for the D1185N mutation shows that an intact MLH3 endonuclease domain is required for somatic CAG expansion. Striatum, 3M n = 5–6, 6M n = 3; liver, 3M n = 5, 6M n = 3; kidney, 3M n = 4–5, 6M n = 2–3; error bars represent standard deviation of the mean; two-way ANOVA (with genotype and tissue as variables) with Tukey multiple comparisons post hoc correction. Genotype effect: ns, not significant; **P < 0.01; ***P < 0.001; ****P < 0.0001. (C) Representative GeneMapper traces across different tissues at 3 and 6 months of age in Htt^Q111 knock-in mice (CAG 121) with different Mlh3 genotypes. 3M: Mlh3^WT/WT, CAG 119, Mlh3^WT/DN and Mlh3^DN/DN, CAG 118. 6M: Mlh3^WT/WT, Mlh3^WT/DN and Mlh3^DN/DN, CAG 121. CAG change from modal allele is represented on the x-axis.