Biallelic mutations in the 3 ' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing


Creative Commons License

Lardelli R. M., Schaffer A. E., Eggens V. R. C., Zaki M. S., Grainger S., Sathe S., ...More

NATURE GENETICS, vol.49, no.3, pp.457-464, 2017 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 49 Issue: 3
  • Publication Date: 2017
  • Doi Number: 10.1038/ng.3762
  • Journal Name: NATURE GENETICS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.457-464
  • Dokuz Eylül University Affiliated: No

Abstract

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknowns. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia(2). We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase(3,4). toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.