title: XIAP variants in male Crohn's disease.
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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Zeissig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Snezana
authors.initials: S
authors.lastname: Milutinovic
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Bosse
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mayr
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Peuker
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Jelka
authors.initials: J
authors.lastname: Hartwig
authors.affiliation: Clinical Bioinformatics, Saarland University, Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
authors.affiliation: Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kohl
authors.affiliation: Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Laass
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Billmann-Born
authors.affiliation: Department of General Pediatrics, University Medical Center Schleswig-Holstein, Lübeck, Germany.
authors.forename: Heide
authors.initials: H
authors.lastname: Brandau
authors.affiliation: Institute of Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
authors.affiliation: Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
mesh_terms: D000293:Adolescent; D003424:Crohn Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human
keywords: Crohn's Disease; GUT Inflammation; Gene Mutation; IBD; Immunodeficiency