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.; Lek, M.; Cummings, B.; Tukiainen, T.; Haritunians, T.; Halme, L.; Koskinen, L. L. E.; Ananthakrishnan, A. N.; Luo, Y.; Heap, G. A.; Visschedijk, M. C.; Macarthur, D. G.; Neale, B. M.; Ahmad, T.; Anderson, C. A.; Brant, S. R.; Duerr, R. H.; Silverberg, M. S.; Cho, J. H.; Palotie, A.; Saavalainen, P.; Kontula, K.; Farkkila, M.; Mcgovern, D. P. B.; Franke, A.; Stefansson, K.; Rioux, J. D.; Xavier, R. J.; Daly, M. J.; Barrett, J.; De Lane, K.; Edwards, C.; Hart, A.; Hawkey, C.; Jostins, L.; Kennedy, N.; Lamb, C.; Lee, J.; Lees, C.; Mansfield, J.; Mathew, C.; Mowatt, C.; Newman, B.; Nimmo, E.; Parkes, M.; Pollard, M.; Prescott, N.; Randall, J.; Rice, D.; Satsangi, J.; Simmons, A.; Tremelling, M.; Uhlig, H.; Wilson, D.; Abraham, C.; Achkar, J. P.; Bitton, A.; Boucher, G.; Croitoru, K.; Fleshner, P.; Glas, J.; Kugathasan, S.; Limbergen, J. V.; Milgrom, R.; Proctor, D.; Regueiro, M.; Schumm, P. L.; Sharma, Y.; Stempak, J. M.; Targan, S. R.; Wang, M. H.. - 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/166131
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