CCGCGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity. Issue 11 (11th October 2021)

• Record Type: Journal Article
• Authors: Perez, Barbara A; Shorrock, Hannah K; Banez‐Coronel, 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
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 11(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-11
• Subjects: cis‐modifier -- RAN translation -- reduced penetrance -- sequence interruptions -- spinocerebellar ataxia type 8; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202114095
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTGCAG 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 CCGCGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCGCGG interruptions correlates with age at onset. At the molecular level, CCGCGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p‐eIF2α and polyAla and polySer RAN protein levels. Additionally, CCGCGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCGCGG 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. SYNOPSIS: This study shows CCGCGG interruptions within the ATXN8OS/ATXN8 CTGCAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8). CCG CGG interruptions in the ATXN8OS/ATXN8 CTGCAG repeat expansion are more frequent in families with multiple affected individuals. The number of CCGCGG interruptions, and not repeat length, correlates with age of onset in SCA8. CGG interrupted ATXN8 repeat expansions are more toxic to cells than pure ATXN8 repeat expansions. CGG interruptions increase RNA stability, p‐eIF2α levels and the levels of toxic polyAla and polySer repeat‐associated non‐AUG (RAN) proteins. Arginine‐interrupted polyGln expansion proteins expressed from CGG interrupted expansions are more toxic than pure polyGln expansion proteins. Abstract : This study shows CCGCGG interruptions within the ATXN8OS/ATXN8 CTGCAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8).