NOX1 loss-of-function genetic variants in patients with inflammatory bowel diseaseMore about Open Access at the Crick
Authors listT Schwerd RV Bryant S Pandey M Capitani Laween Meran J-B Cazier J Jung K Mondal M Parkes CG Mathew K Fiedler DJ McCarthy WGS500 Consortium Oxford IBD cohort study investigators COLORS in IBD UK IBD Genetics Consortium PB Sullivan A Rodrigues SPL Travis Christopher Moore J Sambrook WH Ouwehand DJ Roberts J Danesh INTERVAL Study RK Russell DC Wilson JR Kelsen R Cornall LA Denson S Kugathasan UG Knaus EG Serra CA Anderson RH Duerr DPB McGovern J Cho F Powrie Vivian Li AM Muise HH Uhlig
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Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.
Journal Mucosal Immunology
Issue number 2