TY - JOUR
T1 - CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity
AU - Perez, Barbara A.
AU - Shorrock, Hannah K.
AU - Banez-Coronel, Monica
AU - Zu, Tao
AU - Romano, Lisa E.L.
AU - Laboissonniere, Lauren A.
AU - Reid, Tammy
AU - Ikeda, Yoshio
AU - Reddy, Kaalak
AU - Gomez, Christopher M.
AU - Bird, Thomas
AU - Ashizawa, Tetsuo
AU - Schut, Lawrence J.
AU - Brusco, Alfredo
AU - Berglund, J. Andrew
AU - Hasholt, Lis F.
AU - Nielsen, Jorgen E.
AU - Subramony, S. H.
AU - Ranum, Laura P.W.
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/11/8
Y1 - 2021/11/8
N2 - 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.
AB - 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.
KW - RAN translation
KW - cis-modifier
KW - reduced penetrance
KW - sequence interruptions
KW - spinocerebellar ataxia type 8
KW - Humans
KW - Penetrance
KW - Trinucleotide Repeat Expansion
KW - Proteins
KW - RNA, Long Noncoding/genetics
KW - Spinocerebellar Degenerations/genetics
KW - Nerve Tissue Proteins/genetics
KW - Ataxia
UR - http://www.scopus.com/inward/record.url?scp=85116739014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116739014&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114095
DO - 10.15252/emmm.202114095
M3 - Article
C2 - 34632710
AN - SCOPUS:85116739014
SN - 1757-4676
VL - 13
SP - e14095
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 11
M1 - e14095
ER -