CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity
| Autor: | Christopher M. Gomez, Lawrence J. Schut, Yoshio Ikeda, Lisa E.L. Romano, Tetsuo Ashizawa, Tammy Reid, Lis Hasholt, Tao Zu, Thomas D. Bird, Kaalak Reddy, S Subramony, Barbara A. Perez, J. Andrew Berglund, Laura P.W. Ranum, Jørgen E. Nielsen, Hannah K. Shorrock, Lauren A. Laboissonniere, Monica Banez-Coronel, Alfredo Brusco |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Medicine (General)
congenital hereditary and neonatal diseases and abnormalities Ataxia cis‐modifier Spinocerebellar Degenerations/genetics cis-modifier Nerve Tissue Proteins Penetrance Disease QH426-470 Biology medicine.disease_cause Article R5-920 RAN translation Genetics medicine Nerve Tissue Proteins/genetics Humans RNA Long Noncoding/genetics sequence interruptions Spinocerebellar Degenerations Mutation Proteins Articles medicine.disease reduced penetrance nervous system diseases Protein toxicity spinocerebellar ataxia type 8 Ran Spinocerebellar ataxia Molecular Medicine RNA Long Noncoding Genetics Gene Therapy & Genetic Disease medicine.symptom Trinucleotide repeat expansion Trinucleotide Repeat Expansion Neuroscience |
| Zdroj: | EMBO Molecular Medicine Perez, B A, Shorrock, H K, Banez-Coronel, M, Zu, T, Romano, L E, Laboissonniere, L A, Reid, T, Ikeda, Y, Reddy, K, Gomez, C M, Bird, T, Ashizawa, T, Schut, L J, Brusco, A, Berglund, J A, Hasholt, L F, Nielsen, J E, Subramony, S H & Ranum, L P 2021, ' CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity ', EMBO Molecular Medicine, vol. 13, no. 11, e14095 . https://doi.org/10.15252/emmm.202114095 EMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021) |
| ISSN: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.202114095 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text