Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2
| العنوان: | Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2 |
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| المؤلفون: | 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 |
| المصدر: | Cold Spring Harbor Molecular Case Studies Cold Spring Harbor Molecular Case Studies, 5 Cold Spring Harbor Molecular Case Studies, 5, 1 |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2373-2873 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8225ad4fbca7877a36ccbf8bcb8d0917Test https://hdl.handle.net/21.11116/0000-0003-210A-D21.11116/0000-0003-210C-BTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8225ad4fbca7877a36ccbf8bcb8d0917 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23732873 |
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