CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity
Abstract 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 betwe...
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Wiley
2021
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oai:doaj.org-article:33aca9ac8dc84150a7d6116bee01440f2021-11-08T09:27:45ZCCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity1757-46841757-467610.15252/emmm.202114095https://doaj.org/article/33aca9ac8dc84150a7d6116bee01440f2021-11-01T00:00:00Zhttps://doi.org/10.15252/emmm.202114095https://doaj.org/toc/1757-4676https://doaj.org/toc/1757-4684Abstract 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.Barbara A PerezHannah K ShorrockMonica Banez‐CoronelTao ZuLisa EL RomanoLauren A LaboissonniereTammy ReidYoshio IkedaKaalak ReddyChristopher M GomezThomas BirdTetsuo AshizawaLawrence J SchutAlfredo BruscoJ Andrew BerglundLis F HasholtJorgen E NielsenSH SubramonyLaura PW RanumWileyarticlecis‐modifierRAN translationreduced penetrancesequence interruptionsspinocerebellar ataxia type 8Medicine (General)R5-920GeneticsQH426-470ENEMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
cis‐modifier RAN translation reduced penetrance sequence interruptions spinocerebellar ataxia type 8 Medicine (General) R5-920 Genetics QH426-470 |
| spellingShingle |
cis‐modifier RAN translation reduced penetrance sequence interruptions spinocerebellar ataxia type 8 Medicine (General) R5-920 Genetics QH426-470 Barbara A Perez Hannah K Shorrock Monica Banez‐Coronel Tao Zu Lisa EL Romano Lauren A Laboissonniere Tammy Reid Yoshio Ikeda Kaalak Reddy Christopher M Gomez Thomas Bird Tetsuo Ashizawa Lawrence J Schut Alfredo Brusco J Andrew Berglund Lis F Hasholt Jorgen E Nielsen SH Subramony Laura PW Ranum CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| description |
Abstract 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. |
| format |
article |
| author |
Barbara A Perez Hannah K Shorrock Monica Banez‐Coronel Tao Zu Lisa EL Romano Lauren A Laboissonniere Tammy Reid Yoshio Ikeda Kaalak Reddy Christopher M Gomez Thomas Bird Tetsuo Ashizawa Lawrence J Schut Alfredo Brusco J Andrew Berglund Lis F Hasholt Jorgen E Nielsen SH Subramony Laura PW Ranum |
| author_facet |
Barbara A Perez Hannah K Shorrock Monica Banez‐Coronel Tao Zu Lisa EL Romano Lauren A Laboissonniere Tammy Reid Yoshio Ikeda Kaalak Reddy Christopher M Gomez Thomas Bird Tetsuo Ashizawa Lawrence J Schut Alfredo Brusco J Andrew Berglund Lis F Hasholt Jorgen E Nielsen SH Subramony Laura PW Ranum |
| author_sort |
Barbara A Perez |
| title |
CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| title_short |
CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| title_full |
CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| title_fullStr |
CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| title_full_unstemmed |
CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity |
| title_sort |
ccg•cgg interruptions in high‐penetrance sca8 families increase ran translation and protein toxicity |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/33aca9ac8dc84150a7d6116bee01440f |
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| _version_ |
1718442700296945664 |