Yvonne Zeissig1, Britt-Sabina Petersen2, Snezana Milutinovic3, Esther Bosse4, Gabriele Mayr2, Kenneth Peuker4, Jelka Hartwig4, Andreas Keller5, Martina Kohl6, Martin W Laass7, Susanne Billmann-Born2, Heide Brandau8, Alfred C Feller9, Christoph Röcken10, Martin Schrappe6, Philip Rosenstiel2, John C Reed3, Stefan Schreiber11, Andre Franke2, Sebastian Zeissig4. 1. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. 2. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. 3. Sanford-Burnham Medical Research Institute, La Jolla, California, USA. 4. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany. 5. Clinical Bioinformatics, Saarland University, Saarbrücken, Germany. 6. Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany. 7. Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany. 8. Department of General Pediatrics, University Medical Center Schleswig-Holstein, Lübeck, Germany. 9. Institute of Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany. 10. Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany. 11. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Abstract
OBJECTIVE: The genetic basis of inflammatory bowel disease (IBD) is incompletely understood. The aim of this study was to identify rare genetic variants involved in the pathogenesis of IBD. DESIGN: Exome sequencing and immunological profiling were performed in a patient with early onset Crohn's disease (CD). The coding region of the gene encoding X-linked inhibitor of apoptosis protein (XIAP) was sequenced in samples of 275 paediatric IBD and 1047 adult-onset CD patients. XIAP genotyping was performed in samples of 2680 IBD patients and 2864 healthy controls. Functional effects of the variants identified were investigated in primary cells and cultured cell lines. RESULTS: Our results demonstrate the frequent occurrence of private variants in XIAP in about four percent of male patients with paediatric-onset CD. While XIAP mutations are known to be associated with the primary immunodeficiency (PID) X-linked lymphoproliferative disease type 2 (XLP2), CD patients described here exhibited intestinal inflammation in the absence of XLP2 and harboured a spectrum of mutations partially distinct from that observed in XLP2. The majority of XIAP variants identified was associated with a selective defect in NOD1/2 signalling, impaired NOD1/2-mediated activation of NF-κB, and altered NF-κB-dependent cytokine production. CONCLUSIONS: This study reveals the unanticipated, frequent occurrence of XIAP variants in male paediatric-onset CD. The link between XIAP and NOD1/2, and the association of XIAP variants with XLP2, support the concept of PID in a subset of IBD patients. Moreover, these studies provide a rationale for the implementation of XIAP sequencing in clinical diagnostics in male patients with severe CD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: The genetic basis of inflammatory bowel disease (IBD) is incompletely understood. The aim of this study was to identify rare genetic variants involved in the pathogenesis of IBD. DESIGN: Exome sequencing and immunological profiling were performed in a patient with early onset Crohn's disease (CD). The coding region of the gene encoding X-linked inhibitor of apoptosis protein (XIAP) was sequenced in samples of 275 paediatric IBD and 1047 adult-onset CDpatients. XIAP genotyping was performed in samples of 2680 IBDpatients and 2864 healthy controls. Functional effects of the variants identified were investigated in primary cells and cultured cell lines. RESULTS: Our results demonstrate the frequent occurrence of private variants in XIAP in about four percent of male patients with paediatric-onset CD. While XIAP mutations are known to be associated with the primary immunodeficiency (PID) X-linked lymphoproliferative disease type 2 (XLP2), CDpatients described here exhibited intestinal inflammation in the absence of XLP2 and harboured a spectrum of mutations partially distinct from that observed in XLP2. The majority of XIAP variants identified was associated with a selective defect in NOD1/2 signalling, impaired NOD1/2-mediated activation of NF-κB, and altered NF-κB-dependent cytokine production. CONCLUSIONS: This study reveals the unanticipated, frequent occurrence of XIAP variants in male paediatric-onset CD. The link between XIAP and NOD1/2, and the association of XIAP variants with XLP2, support the concept of PID in a subset of IBDpatients. Moreover, these studies provide a rationale for the implementation of XIAP sequencing in clinical diagnostics in male patients with severe CD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Crohn's Disease; GUT Inflammation; Gene Mutation; IBD; Immunodeficiency
Authors: Sebastian Zeissig; Britt-Sabina Petersen; Michal Tomczak; Espen Melum; Emilie Huc-Claustre; Stephanie K Dougan; Jon K Laerdahl; Björn Stade; Michael Forster; Stefan Schreiber; Dascha Weir; Alan M Leichtner; Andre Franke; Richard S Blumberg Journal: Gut Date: 2014-11-03 Impact factor: 23.059
Authors: Steven M Chirieleison; Rebecca A Marsh; Prathna Kumar; Joseph K Rathkey; George R Dubyak; Derek W Abbott Journal: J Biol Chem Date: 2017-04-12 Impact factor: 5.157
Authors: Asama Lekbua; Jodie Ouahed; Amy E O'Connell; Stacy A Kahn; Jeffrey D Goldsmith; Toshihiko Imamura; Christine N Duncan; Judith R Kelsen; Elizabeth Worthey; Scott B Snapper; Samir Softic Journal: J Pediatr Gastroenterol Nutr Date: 2019-07 Impact factor: 2.839
Authors: Kaida Ning; Kyle Gettler; Wei Zhang; Sok Meng Ng; B Monica Bowen; Jeffrey Hyams; Michael C Stephens; Subra Kugathasan; Lee A Denson; Eric E Schadt; Gabriel E Hoffman; Judy H Cho Journal: Hum Mol Genet Date: 2015-05-01 Impact factor: 6.150