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. By 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.

中文翻译：

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在亨廷顿病基因敲除小鼠中，Fan1 敲除对体细胞 CAG 重复扩增的促进被 Mlh1 敲除阻止。

最近对亨廷顿病 (HD) 发病年龄的全基因组关联研究指出了潜在疾病修饰的不同模式：改变HTT CAG 重复的体细胞扩增速率或改变由此产生的 CAG 阈值长度触发的毒性过程。在这里，我们评估了两种 HD 发病年龄修饰基因FAN1和RRM2B的小鼠直向同源物，以研究对Htt CAG 敲入小鼠中扩增的 CAG 重复序列的体细胞不稳定性的影响。Fan1敲除增加了Htt CAG 重复的体细胞扩增，在青少年和成人发病的 HD 范围内，而Rrm2b 的敲除并没有显着改变体细胞HttCAG 重复不稳定。同时敲除Mlh1，即第三个 HD 发病年龄修饰基因 ( MLH1 )的直系同源基因，抑制Htt敲入 CAG 重复序列的体细胞扩增，阻止Fan1敲除诱导的体细胞 CAG 扩增加速. 这种遗传相互作用表明 FAN1 丢失的 CAG 重复不稳定效应需要功能性 MLH1。因此，在 HD 中，不确定RRM2B修饰剂对发病时间的影响是否可能是由于 DNA 不稳定机制。相比之下，FAN1 修饰符效应表明，功能性 FAN1 可抑制体细胞 CAG 重复扩增，这可能与其他 DNA 不稳定性修饰符的遗传相互作用有关，这些修饰符的组合效应可以加速或延迟发作和其他 CAG 重复长度驱动的表型。