Article Text

other Versions

PDF
Original article
XIAP variants in male Crohn's disease
  1. Yvonne Zeissig1,2,3,
  2. Britt-Sabina Petersen3,
  3. Snezana Milutinovic4,
  4. Esther Bosse1,
  5. Gabriele Mayr3,
  6. Kenneth Peuker1,
  7. Jelka Hartwig1,
  8. Andreas Keller5,
  9. Martina Kohl2,
  10. Martin W Laass6,
  11. Susanne Billmann-Born3,
  12. Heide Brandau7,
  13. Alfred C Feller8,
  14. Christoph Röcken9,
  15. Martin Schrappe2,
  16. Philip Rosenstiel3,
  17. John C Reed4,
  18. Stefan Schreiber1,3,
  19. Andre Franke3,
  20. Sebastian Zeissig1
  1. 1Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
  2. 2Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
  3. 3Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  4. 4Sanford-Burnham Medical Research Institute, La Jolla, California, USA
  5. 5Clinical Bioinformatics, Saarland University, Saarbrücken, Germany
  6. 6Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany
  7. 7Department of General Pediatrics, University Medical Center Schleswig-Holstein, Lübeck, Germany
  8. 8Institute of Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany
  9. 9Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany
  1. Correspondence to Dr Sebastian Zeissig, Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Schittenhelmstr. 12, Kiel 24105, Germany; szeissig{at}1med.uni-kiel.de and Dr Andre Franke, Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany; a.franke{at}mucosa.de

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.

  • Gene Mutation
  • GUT Inflammation
  • IBD
  • Immunodeficiency
  • Crohn's Disease

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.