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BACKGROUND & AIMS: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD. METHODS: After targeted exome sequencing of epithelial NADPH oxidasesNOX1andDUOX2on 209 children with very early onset inflammatory bowel disease (VEOIBD), the identified mutations were validated using Sanger Sequencing. A structural analysis ofNOX1andDUOX2variants was performed by homology in silico modeling. The functional characterization included ROS generation in model cell lines and in in vivo transduced murine crypts, protein expression, intracellular localization, and cell-based infection studies with the enteric pathogensCampylobacter jejuniand enteropathogenicEscherichia coli. RESULTS: We identified missense mutations inNOX1(c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn) andDUOX2(c.4474G>A, p.Arg1211Cys; c.3631C>T, p.Arg1492Cys) in 5 of 209 VEOIBD patients. TheNOX1p.Asp360Asn variant was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. AllNOX1andDUOX2variants showed reduced ROS production compared with wild-type enzymes. Despite appropriate cellular localization and comparable pathogen-stimulated translocation of altered oxidases, cells harboringNOX1orDUOX2variants had defective host resistance to infection withC. jejuni. CONCLUSIONS: This study identifies the first inactivating missense variants inNOX1andDUOX2associated with VEOIBD. Defective ROS production from intestinal epithelial cells constitutes a risk factor for developing VEOIBD.

Original publication




Journal article


Cell Mol Gastroenterol Hepatol

Publication Date





489 - 502


DUOX2, Inflammatory Bowel Disease, NADPH Oxidase, NOX1, Reactive Oxygen Species, VEOIBD