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Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2

Lookup NU author(s): Professor Joris VeltmanORCiD


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© 2019 Lipinski et al.; Published by Cold Spring Harbor Laboratory Press. Whole-genome and whole-exome sequencing of individual patients allow the study of rare and potentially causative genetic variation. In this study, we sequenced DNA of a trio comprising a boy with very-early-onset inflammatory bowel disease (veoIBD) and his unaffected parents. We identified a rare, X-linked missense variant in the NAPDH oxidase NOX1 gene (c.C721T, p.R241C) in heterozygous state in the mother and in hemizygous state in the patient. We discovered that, in addition, the patient was homozygous for a common missense variant in the CYBA gene (c.T214C, p.Y72H). CYBA encodes the p22phox protein, a cofactor for NOX1. Functional assays revealed reduced cellular ROS generation and antibacterial capacity of NOX1 and p22phox variants in intestinal epithelial cells. Moreover, the identified NADPH oxidase complex variants affected NOD2-mediated immune responses, and p22phox was identified as a novel NOD2 interactor. In conclusion, we detected missense variants in a veoIBD patient that disrupt the host response to bacterial challenges and reduce protective innate immune signaling via NOD2. We assume that the patient's individual genetic makeup favored disturbed intestinal mucosal barrier function.

Publication metadata

Author(s): Lipinski S, Petersen B-S, Barann M, Piecyk A, Tran F, Mayr G, Jentzsch M, Aden K, Stengel ST, Klostermeier UC, Sheth V, Ellinghaus D, Rausch T, Korbel JO, Nothnagel M, Krawczak M, Gilissen C, Veltman JA, Forster M, Forster P, Lee CC, Fritscher-Ravens A, Schreiber S, Franke A, Rosenstiel P

Publication type: Article

Publication status: Published

Journal: Cold Spring Harbor Molecular Case Studies

Year: 2019

Volume: 5

Issue: 1

Online publication date: 01/02/2019

Acceptance date: 29/10/2018

ISSN (electronic): 2373-2873

Publisher: Cold Spring Harbor Laboratory Press


DOI: 10.1101/mcs.a002428

PubMed id: 30709874


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