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 â '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.
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis / Rivas, M.A., Graham, D., Sulem, P., Stevens, C., Desch, A.N., Goyette, P., Gudbjartsson, D., Jonsdottir, I., Thorsteinsdottir, U., Degenhardt, F., Mucha, S., Kurki, M.I., Li, D., D'Amato, M., Annese, V., Vermeire, S., Weersma, R.K., Halfvarson, J., Paavola-Sakki, P., Lappalainen, M., et al.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 7:(2016). [10.1038/ncomms12342]
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Annese V.;
2016-01-01
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 â '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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
