NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., WGS500 Consortium, Oxford IBD cohort study investigators, COLORS in IBD group investigators, UK IBD Genetics Consortium, Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., INTERVAL Study, Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P., Cho, J., Powrie, F., Li, V. S., Muise, A. M., & Uhlig, H. H. Mucosal Immunology, 11(2):562–574, 2018.
doi  abstract   bibtex   
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.
@article{schwerd_nox1_2018,
	title = {{NOX1} loss-of-function genetic variants in patients with inflammatory bowel disease},
	volume = {11},
	issn = {1935-3456},
	doi = {10.1038/mi.2017.74},
	abstract = {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.},
	language = {eng},
	number = {2},
	journal = {Mucosal Immunology},
	author = {Schwerd, T. and Bryant, R. V. and Pandey, S. and Capitani, M. and Meran, L. and Cazier, J.-B. and Jung, J. and Mondal, K. and Parkes, M. and Mathew, C. G. and Fiedler, K. and McCarthy, D. J. and {WGS500 Consortium} and {Oxford IBD cohort study investigators} and {COLORS in IBD group investigators} and {UK IBD Genetics Consortium} and Sullivan, P. B. and Rodrigues, A. and Travis, S. P. L. and Moore, C. and Sambrook, J. and Ouwehand, W. H. and Roberts, D. J. and Danesh, J. and {INTERVAL Study} and Russell, R. K. and Wilson, D. C. and Kelsen, J. R. and Cornall, R. and Denson, L. A. and Kugathasan, S. and Knaus, U. G. and Serra, E. G. and Anderson, C. A. and Duerr, R. H. and McGovern, D. Pb and Cho, J. and Powrie, F. and Li, V. Sw and Muise, A. M. and Uhlig, H. H.},
	year = {2018},
	pmid = {29091079},
	pmcid = {PMC5924597},
	keywords = {*Genotype, Animals, Child, Child, Preschool, Colon, Colon/*physiology, Genes, Modifier, Genes, Modifier/*genetics, Genetic Association Studies, Genetic Predisposition to Disease, Genome, Genotype, High-Throughput Nucleotide Sequencing, Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Inflammatory Bowel Diseases/*genetics, Male, Mice, Mice, Inbred C57BL, Mutation, Missense, Mutation, Missense/genetics, NADPH Oxidase 1, NADPH Oxidase 1/*genetics, Polymorphism, Single Nucleotide, Reactive Oxygen Species, Reactive Oxygen Species/metabolism},
	pages = {562--574}
}

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