Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2
| Autor: | Marlene Jentzsch, Michael Nothnagel, Ulrich C. Klostermeier, Joris A. Veltman, Vrunda Sheth, Clarence C. Lee, Christian Gilissen, Simone Lipinski, Agnes Piecyk, Britt-Sabina Petersen, David Ellinghaus, Michael Krawczak, Jan O. Korbel, Konrad Aden, Michael Forster, Matthias Barann, Philip Rosenstiel, Annette Fritscher-Ravens, Florian Tran, Gabriele Mayr, Stephanie T. Stengel, Tobias Rausch, Andre Franke, Peter Forster, Stefan Schreiber |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Research Report Mutation Missense Nod2 Signaling Adaptor Protein Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine Immune system All institutes and research themes of the Radboud University Medical Center NOD2 Cell Line Tumor Genetic variation Exome Sequencing Missense mutation Humans Gene 030304 developmental biology Genetics 0303 health sciences Chromosomes Human X Innate immune system Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] biology Whole Genome Sequencing Homozygote NADPH Oxidases Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine Inflammatory Bowel Diseases 3. Good health inflammation of the large intestine 030220 oncology & carcinogenesis NOX1 biology.protein NADPH Oxidase 1 P22phox |
| Zdroj: | Cold Spring Harbor Molecular Case Studies Cold Spring Harbor Molecular Case Studies, 5 Cold Spring Harbor Molecular Case Studies, 5, 1 |
| ISSN: | 2373-2873 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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