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

EMBO Mol Med. 2021 Nov 8;13(11):e14095. doi: 10.15252/emmm.202114095. Epub 2021 Oct 11.


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: RAN translation; cis-modifier; reduced penetrance; sequence interruptions; spinocerebellar ataxia type 8.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia
  • Humans
  • Nerve Tissue Proteins / genetics
  • Penetrance
  • Proteins
  • RNA, Long Noncoding / genetics
  • Spinocerebellar Degenerations* / genetics
  • Trinucleotide Repeat Expansion*


  • ATXN8 protein, human
  • ATXN8OS gene product, human
  • Nerve Tissue Proteins
  • Proteins
  • RNA, Long Noncoding