Universität zu Köln

Lipinski, Simone, Petersen, Britt-Sabina, Barann, Matthias, Piecyk, Agnes ORCID: 0000-0002-9582-121X, Tran, Florian, Mayr, Gabriele, Jentzsch, Marlene, Aden, Konrad ORCID: 0000-0003-3482-7316, Stengel, Stephanie T., Klostermeier, Ulrich C., Sheth, Vrunda, Ellinghaus, David, Rausch, Tobias ORCID: 0000-0001-5773-5620, Korbel, Jan O., Nothnagel, Michael ORCID: 0000-0001-8305-7114, Krawczak, Michael ORCID: 0000-0003-2603-1502, Gilissen, Christian ORCID: 0000-0003-1693-9699, Veltman, Joris A., Forster, Michael ORCID: 0000-0001-9927-5124, Forster, Peter, Lee, Clarence C., Fritscher-Ravens, Annette, Schreiber, Stefan, Franke, Andre and Rosenstiel, Philip ORCID: 0000-0002-9692-8828 (2019). Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2. Cold Spring Harb. Mol. Case Stud., 5 (1). COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 2373-2873

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lipinski, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Petersen, Britt-Sabina UNSPECIFIED UNSPECIFIED UNSPECIFIED Barann, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Piecyk, Agnes UNSPECIFIED orcid.org/0000-0002-9582-121X UNSPECIFIED Tran, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Jentzsch, Marlene UNSPECIFIED UNSPECIFIED UNSPECIFIED Aden, Konrad UNSPECIFIED orcid.org/0000-0003-3482-7316 UNSPECIFIED Stengel, Stephanie T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klostermeier, Ulrich C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sheth, Vrunda UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellinghaus, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Rausch, Tobias UNSPECIFIED orcid.org/0000-0001-5773-5620 UNSPECIFIED Korbel, Jan O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED Krawczak, Michael UNSPECIFIED orcid.org/0000-0003-2603-1502 UNSPECIFIED Gilissen, Christian UNSPECIFIED orcid.org/0000-0003-1693-9699 UNSPECIFIED Veltman, Joris A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Forster, Michael UNSPECIFIED orcid.org/0000-0001-9927-5124 UNSPECIFIED Forster, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Clarence C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fritscher-Ravens, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Schreiber, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenstiel, Philip UNSPECIFIED orcid.org/0000-0002-9692-8828 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-158050
DOI:	10.1101/mcs.a002428
Journal or Publication Title:	Cold Spring Harb. Mol. Case Stud.
Volume:	5
Number:	1
Date:	2019
Publisher:	COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication:	COLD SPRING HARBOR
ISSN:	2373-2873
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NADPH OXIDASE; CROHNS-DISEASE; GENETIC-VARIATION; RECEPTOR 1; EXPRESSION; MUTATIONS; SUSCEPTIBILITY; GENERATION; PROTEIN; GUT Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15805