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.

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

Brusco A.;
2021-01-01

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.
2021
e14095
1
15
https://www.embopress.org/doi/full/10.15252/emmm.202114095
cis-modifier; RAN translation; reduced penetrance; sequence interruptions; spinocerebellar ataxia type 8
Perez B.A.; Shorrock H.K.; Banez-Coronel M.; Zu T.; Romano L.E.L.; Laboissonniere L.A.; Reid T.; Ikeda Y.; Reddy K.; Gomez C.M.; Bird T.; Ashizawa T.;...espandi
File in questo prodotto:
File Dimensione Formato  
182. SCA8_EMBOMolMed2021.pdf

Accesso aperto

Descrizione: PDF editoriale aperto
Tipo di file: PDF EDITORIALE
Dimensione 6.37 MB
Formato Adobe PDF
6.37 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1815198
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 11
social impact