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

Nat Genet. 2017 Mar;49(3):457-464. doi: 10.1038/ng.3762. Epub 2017 Jan 16.


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 unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. 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.

MeSH terms

  • Alleles
  • Animals
  • Cerebellar Diseases / genetics*
  • Exonucleases / genetics*
  • Female
  • Humans
  • Male
  • Mice
  • Mutation / genetics*
  • Neurodegenerative Diseases / genetics
  • Nuclear Proteins / genetics*
  • RNA, Messenger / genetics
  • RNA, Small Nuclear / genetics*
  • Spliceosomes / genetics
  • Zebrafish


  • Nuclear Proteins
  • RNA, Messenger
  • RNA, Small Nuclear
  • TOE1 protein, human
  • Exonucleases

Supplementary concepts

  • Pontocerebellar Hypoplasia