CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity.
CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity.
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DOI：
10.15252/emmm.202114095
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发表时间：
2021-11-08
影响因子：
11.1
通讯作者：
Ranum LP
中科院分区：
文献类型：
--
作者：
Perez BA;Shorrock HK;Banez-Coronel M;Zu T;Romano LE;Laboissonniere LA;Reid T;Ikeda Y;Reddy K;Gomez CM;Bird T;Ashizawa T;Schut LJ;Brusco A;Berglund JA;Hasholt LF;Nielsen JE;Subramony SH;Ranum LP
脊髓小脑性共济失调8型（SCA8）是一种由CTG•CAG扩增引起的显性遗传性神经退行性疾病，它不常见，因为大多数携带该突变的个体不会发生共济失调。为了了解SCA8的可变外显率，我们使用一个大型的SCA8家族队列（n = 77）研究了高外显家族和更常见的散发病例（82%）之间的分子差异。我们发现，来自多个受影响家庭成员的重复扩增突变个体的CCG•CGG中断的频率高于散发性SCA8病例，并且CCG•CGG中断的数量与发病年龄相关。在分子水平上，CCG•CGG中断增加了RNA发夹的稳定性，在细胞培养实验中，增加了p - eIF2α和polyAla和polySer RAN蛋白水平。此外，在polyGln框架中编码精氨酸中断的CCG•CGG中断会增加所产生的蛋白质的毒性。总之，SCA8 CCG•CGG中断增加了polyAla和polySer RAN蛋白水平、polyGln蛋白毒性和疾病外显率，并为高外显率和低外显率的SCA8家族之间的分子差异提供了新的见解。本研究表明，ATXN8OS/ATXN8 CTG•CAG重复序列中的CCG•CGG中断是脊髓小脑性共济失调8型（SCA8）疾病外显率的重要遗传修饰因子。
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. This study shows CCG•CGG interruptions within the ATXN8OS/ATXN8 CTG•CAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8).
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影响因子：
4.5
作者：
Daughters RS;Tuttle DL;Gao W;Ikeda Y;Moseley ML;Ebner TJ;Swanson MS;Ranum LP
通讯作者：
Ranum LP
影响因子：
3.1
作者：
Kim, Ji Sun;Son, Tae Ok;Cho, Jin Whan
通讯作者：
Cho, Jin Whan
影响因子：
9.8
作者：
Ikeda, Y;Dalton, JC;Ranum, LPW
通讯作者：
Ranum, LPW
影响因子：
16.6
作者：
Green KM;Glineburg MR;Kearse MG;Flores BN;Linsalata AE;Fedak SJ;Goldstrohm AC;Barmada SJ;Todd PK
通讯作者：
Todd PK
影响因子：
30.8
作者：
Koob, MD;Moseley, ML;Ranum, LPW
通讯作者：
Ranum, LPW