CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity.
RAN translation
cis-modifier
reduced penetrance
sequence interruptions
spinocerebellar ataxia type 8
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 11 2021
08 11 2021
Historique:
revised:
09
09
2021
received:
07
02
2021
accepted:
10
09
2021
pubmed:
12
10
2021
medline:
23
11
2021
entrez:
11
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34632710
doi: 10.15252/emmm.202114095
pmc: PMC8573593
doi:
Substances chimiques
ATXN8 protein, human
0
ATXN8OS gene product, human
0
Nerve Tissue Proteins
0
Proteins
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14095Subventions
Organisme : NINDS NIH HHS
ID : R37 NS040389
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS082168
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS117910
Pays : United States
Organisme : NINDS NIH HHS
ID : P50 NS048843
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS040389
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS126536
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS098819
Pays : United States
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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