XIAP variants in male Crohn's disease

Yvonne Zeissig, Britt Sabina Petersen, Snezana Milutinovic, Esther Bosse, Gabriele Mayr, Kenneth Peuker, Jelka Hartwig, Andreas Keller, Martina Kohl, Martin W. Laass, Susanne Billmann-Born, Heide Brandau, Alfred C. Feller, Christoph Röcken, Martin Schrappe, Philip Rosenstiel, John C. Reed, Stefan Schreiber, Andre Franke, Sebastian Zeissig*

*Corresponding author for this work
81 Citations (Scopus)


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.

Original languageEnglish
Issue number1
Pages (from-to)66-76
Number of pages11
Publication statusPublished - 01.01.2015

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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