Open AccessCCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity
Author(s) -
Perez Barbara A,
Shorrock Hannah K,
BanezCoronel Monica,
Zu Tao,
Romano Lisa EL,
Laboissonniere Lauren A,
Reid Tammy,
Ikeda Yoshio,
Reddy Kaalak,
Gomez Christopher M,
Bird Thomas,
Ashizawa Tetsuo,
Schut Lawrence J,
Brusco Alfredo,
Berglund J Andrew,
Hasholt Lis F,
Nielsen Jorgen E,
Subramony SH,
Ranum Laura PW
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114095
Subject(s) - penetrance , spinocerebellar ataxia , genetics , biology , toxicity , mutation , medicine , phenotype , gene
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.