CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. / 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, S H; Ranum, Laura Pw.

I: EMBO Molecular Medicine, Bind 13, Nr. 11, e14095, 08.11.2021.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Perez, BA, Shorrock, HK, Banez-Coronel, M, Zu, T, Romano, LE, Laboissonniere, LA, Reid, T, Ikeda, Y, Reddy, K, Gomez, CM, Bird, T, Ashizawa, T, Schut, LJ, Brusco, A, Berglund, JA, Hasholt, LF, Nielsen, JE, Subramony, SH & Ranum, LP 2021, 'CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity', EMBO Molecular Medicine, bind 13, nr. 11, e14095. https://doi.org/10.15252/emmm.202114095

APA

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, 13(11), [e14095]. https://doi.org/10.15252/emmm.202114095

Vancouver

Perez BA, Shorrock HK, Banez-Coronel M, Zu T, Romano LE, Laboissonniere LA o.a. CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO Molecular Medicine. 2021 nov. 8;13(11). e14095. https://doi.org/10.15252/emmm.202114095

Author

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, S H ; Ranum, Laura Pw. / CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. I: EMBO Molecular Medicine. 2021 ; Bind 13, Nr. 11.

Bibtex

@article{8af2876f7e104febbd4e860929a70dc7,
title = "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 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.",
keywords = "Ataxia, Humans, Nerve Tissue Proteins/genetics, Penetrance, Proteins, RNA, Long Noncoding/genetics, Spinocerebellar Degenerations/genetics, Trinucleotide Repeat Expansion",
author = "Perez, {Barbara A} and Shorrock, {Hannah K} and Monica Banez-Coronel and Tao Zu and Romano, {Lisa El} and Laboissonniere, {Lauren A} and Tammy Reid and Yoshio Ikeda and Kaalak Reddy and Gomez, {Christopher M} and Thomas Bird and Tetsuo Ashizawa and Schut, {Lawrence J} and Alfredo Brusco and Berglund, {J Andrew} and Hasholt, {Lis F} and Nielsen, {Jorgen E} and Subramony, {S H} and Ranum, {Laura Pw}",
note = "{\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2021",
month = nov,
day = "8",
doi = "10.15252/emmm.202114095",
language = "English",
volume = "13",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "11",

}

RIS

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 El

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 Pw

N1 - © 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 - Ataxia

KW - Humans

KW - Nerve Tissue Proteins/genetics

KW - Penetrance

KW - Proteins

KW - RNA, Long Noncoding/genetics

KW - Spinocerebellar Degenerations/genetics

KW - Trinucleotide Repeat Expansion

U2 - 10.15252/emmm.202114095

DO - 10.15252/emmm.202114095

M3 - Journal article

C2 - 34632710

VL - 13

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 11

M1 - e14095

ER -

ID: 297155236