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NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Lookup NU author(s): Dr Chris LambORCiD, Dr John Mansfield



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 Nature Publishing Group. All rights reserved. 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.

Publication metadata

Author(s): Schwerd T, Bryant RV, Pandey S, Capitani M, Meran L, Cazier J-B, Jung J, Mondal K, Parkes M, Mathew CG, Fiedler K, McCarthy DJ, Sullivan PB, Rodrigues A, Travis SPL, Moore C, Sambrook J, Ouwehand WH, Roberts DJ, Danesh J, Russell RK, Wilson DC, Kelsen JR, Cornall R, Denson LA, Kugathasan S, Knaus UG, Serra EG, Anderson CA, Duerr RH, McGovern DPB, Cho J, Powrie F, Li VSW, Muise AM, Uhlig HH, Donnelly P, Bell J, Bentley D, McVean G, Ratcliffe P, Taylor J, Wilkie AOM, Donnelly P, Broxholme J, Buck D, Cazier J-B, Cornall R, Gregory L, Gregory J, Lunter G, McVean G, Taylor J, Tomlinson I, Wilkie AOM, Buck D, Allan C, Attar M, Green A, Gregory L, Humphray S, Kingsbury Z, Lamble S, Lonie L, Pagnamenta A, Piazza P, Polanco G, Trebes A, McVean G, Donnelly P, Cazier J-B, Broxholme J, Copley R, Fiddy S, Grocock R, Hatton E, Holmes C, Hughes L, Humburg P, Kanapin A, Lise S, Lunter G, Martin H, Murray L, McCarthy D, Rimmer A, Sahgal N, Wright B, Yau C, Arancibia C, Bailey A, Barnes E, Bird-Lieberman B, Brain O, Braden B, Collier J, East J, Geremia A, Howarth L, Keshav S, Klenerman P, Leedham S, Palmer R, Powrie F, Rodrigues A, Simmons A, Sullivan PB, Travis SPL, Uhlig HH, Heuschkel R, Zilbauer M, Auth MKH, Shah N, Kammermeier J, Croft N, Barakat F, Russell RK, Wilson DC, Henderson P, Braegger CP, Posovszky C, Fyderek K, Wedrychowicz A, Zurek M, Strisciuglio C, Elawad M, Lo B, Parkes M, Satsangi J, Anderson CA, Jostins L, Kennedy NA, Lamb CA, Ahmad T, Edwards C, Hart A, Hawkey C, Mansfield JC, Mowat C, Newman WG, Satsangi J, Simmons A, Tremelling M, Uhlig HH, Wilson DC, Lee JC, Prescott NJ, Lees CW, Mathew CG, Parkes M, Barrett JC, Anderson CA

Publication type: Article

Publication status: Published

Journal: Mucosal Immunology

Year: 2018

Volume: 11

Issue: 2

Pages: 562-574

Print publication date: 01/03/2018

Online publication date: 01/11/2017

Acceptance date: 20/07/2017

Date deposited: 08/01/2019

ISSN (print): 1933-0219

ISSN (electronic): 1935-3456

Publisher: Nature Publishing Group


DOI: 10.1038/mi.2017.74


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Funder referenceFunder name
Crohn's & Colitis Foundation of America
Boehringer Ingelheim Foundation Grant
Cancer Research UK
Medical Research Council
Francis Crick Institute
Medical Research Foundation
G0900747 91070
General Sir John Monash Foundation
NIHR Biomedical Research Centre Oxford
NIHR Blood and Transplant Research Unit Donor Health and Genomics
NIHR Research Cambridge Biomeidcal Research Centre
P01 DK046763
NHS Research Scotland Senior Fellowship
Science Foundation Article
Oxford BRC
UK Department of Health's NIHR Biomedical Research Centres funding scheme
UK Medical Research Council
R01 DK098231
Wellcome Trust