A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Nat Commun. 2016 Aug 9;7:12342. doi: 10.1038/ncomms12342.

Abstract

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

Publication types

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

MeSH terms

  • Alleles
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / prevention & control*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Mutation / genetics*
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Sequence Analysis, DNA
  • Ubiquitin-Protein Ligases / genetics*

Substances

  • RNA, Messenger
  • RNF186 protein, human
  • Ubiquitin-Protein Ligases