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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Rivas, Manuel A 
Graham, Daniel 
Stevens, Christine 
Desch, A Nicole 

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.

Description

Keywords

Alleles, Colitis, Ulcerative, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Mutation, Protein Transport, RNA, Messenger, Reproducibility of Results, Sequence Analysis, DNA, Ubiquitin-Protein Ligases

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

7

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (091310/Z/10/Z)