期刊
MUCOSAL IMMUNOLOGY
卷 11, 期 2, 页码 562-574出版社
SPRINGERNATURE
DOI: 10.1038/mi.2017.74
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资金
- National Institute of Health Research (NIHR)
- NIHR BioResource
- NIHR Cambridge Biomedical Research Centre
- NIHR Blood and Transplant Research Unit in Donor Health and Genomics
- UK Medical Research Council [G0800270]
- British Heart Foundation [SP/09/002]
- NIHR Research Cambridge Biomedical Research Centre
- Medical Research Fund Oxford
- Deutsche Forschungsgemeinschaft [SCHW1 730/1-1]
- Crohn's & Colitis Foundation of America (CCFA)
- Leona M. and Harry B. Helmsley Charitable Trust
- Crohn's and Colitis UK for Crohns
- Boehringer Ingelheim Foundation grant
- Wellcome Trust [090532/Z/09/Z]
- Science Foundation Ireland
- Illumina
- Oxford BRC
- Francis Crick Institute
- Cancer Research UK
- UK Medical Research Council
- NHS Research Scotland Senior Fellowship
- Medical Research Council and Medical Research Foundation for PICTS
- National Institutes of Health [K23DK100461 01A1]
- Medical Research Council Hub grant [G0900747 91070]
- NIHR Biomedical Research Centre Oxford
- UK Department of Health's NIHR Biomedical Research Centres
- General Sir John Monash Foundation, Australia
- [RO1 DK098231]
- [P01 DK046763]
- [DK06241 3]
- Academy of Medical Sciences (AMS) [AMS-SGCL7-Bird-Lieberman] Funding Source: researchfish
- Alan Turing Institute [TU/B/000062] Funding Source: researchfish
- British Heart Foundation [RG/13/13/30194] Funding Source: researchfish
- Chief Scientist Office [ETM/137] Funding Source: researchfish
- Crohn's and Colitis UK [M11-1] Funding Source: researchfish
- Medical Research Council [G0800675, G0600329, G0800270, MC_UU_00008/7, HDR-4004, HDR-1004, G0800759, MC_UU_12010/7, MC_UP_1202/7, MC_UU_12010/6, MR/L003120/1, MC_UU_00008/6, MC_UP_A390_1107] Funding Source: researchfish
- Medical Research Foundation [C0482] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10005, NF-SI-0512-10165, NF-SI-0513-10151, CL-2014-01-005, NF-SI-0617-10113, NIHR-RP-R3-12-026] Funding Source: researchfish
- The Francis Crick Institute [668294 - INTENS, 10105] Funding Source: researchfish
- Wellcome Trust [102974/Z/13/Z, 109965/Z/15/Z, 101734/Z/13/Z] Funding Source: researchfish
- MRC [MC_UU_00008/7, G0800759, MC_UP_A390_1107, G0800270, MC_UP_1202/7, G0600329, G0800675, MR/L003120/1, MC_UU_00008/6, MC_UU_12010/6, MC_UU_12010/7] Funding Source: UKRI
- Wellcome Trust [101734/Z/13/Z] Funding Source: Wellcome Trust
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.
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