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

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Authors
Rivas, M A
Graham, D
Sulem, P
Stevens, C
Desch, A N
Goyette, P
Gudbjartsson, D
Jonsdottir, I
Thorsteinsdottir, U
Degenhardt, F
Journal
Nature Communications
Type
Journal Article
Publisher
Nature
Rights
Archived with thanks to Nature communications. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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.
Citation
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. 2016, 7:12342 Nat Commun
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