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. 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 paediatriconset 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.

X-linked Inhibitor of Apoptosis Protein Deficiency: More than an X-linked Lymphoproliferative Syndrome

“…It is noteworthy that we recently found XIAP mutations in a relatively high proportion (4 %) of a pediatric cohort of 83 boys with IBD [9]. A fairly similar prevalence was also observed in a German pediatric cohort of patients with IBD [10]. Diagnosis of a XIAP mutation must prompt the analysis of family members and thus the identification of male and female carriers.…”

“…The age at onset of IBD varies greatly from 3 months to 41 years [9]. The clinical presentation and the biological and histological features are very similar to those observed in adult patients with Crohn's disease [9,10]. In fact, the IBD can be very severe and is often resistant to various treatments.…”

“…NOD1/2 receptors are directly coupled to RIPK2 and ubiquitylation of RIPK2 by XIAP promotes the recruitment of the linear ubiquitin chain assembly complex (LUBAC), which in turns activates NFκB signaling and cytokine production [22,40,30]. We and others have reported that XIAP-deficient monocytes from patients display an impaired production of cytokines and chemokines (including TNF-α, IL-10, IL-8 and MCP-1) in response to stimulation with NOD2 ligands [9][10][11]. Furthermore, fibroblasts from XIAP-deficient patients also show defective production of IL-8 and IL-6 in response to NOD1 activation [9].…”

“…IBD is also a prevalent phenotype and affecting 25-30 % of patients. IBD can occur before HLH and may be the first and the only symptom of the disease [9,8,11,10]. The age at onset of IBD varies greatly from 3 months to 41 years [9].…”

“…A few XLP-2 patients have developed variable, auto-inflammatory-like symptoms not shared by XLP-1 patients. Recently, young boys with earlyonset IBD as the only clinical trait were reported to be carriers of inactivating XIAP mutations -thus confirming the predominant role of XIAP deficiency in the occurrence of IBD [9][10][11]. Hence, XIAP deficiency should be now considered as one of the Mendelian determinants of inherited IBD in infancy [12].…”