Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.

中文翻译：

---

高外显率 SCA8 家族中的 CCG•CGG 中断会增加 RAN 翻译和蛋白质毒性

脊髓小脑性共济失调 8 型 (SCA8) 是一种由 CTG•CAG 扩张引起的显性遗传性神经退行性疾病，它很不寻常，因为大多数携带该突变的个体不会出现共济失调。为了了解 SCA8 的可变外显率，我们使用大量 SCA8 家族 ( n  = 77) 研究了高外显家族和更常见散发病例 (82%) 之间的分子差异。我们发现，来自多个受影响家庭成员的个体的重复扩增突变比散发的 SCA8 病例具有更高的 CCG•CGG 中断频率，并且 CCG•CGG 中断的数量与发病年龄相关。在分子水平上，CCG•CGG 中断可提高 RNA 发夹的稳定性，在细胞培养实验中，可提高 p-eIF2α 以及 polyAla 和 polySer RAN 蛋白水平。此外，CCG•CGG 中断编码聚谷氨酰胺框架中的精氨酸中断，会增加所得蛋白质的毒性。总之，SCA8 CCG•CGG 中断增加了聚丙氨酸和聚丝氨酸 RAN 蛋白水平、聚谷氨酰胺蛋白毒性和疾病外显率，并为高疾病外显率与低疾病外显率的 SCA8 家族之间的分子差异提供了新的见解。