Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.

Chloride-proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue cattle with a severe symptomatology including perinatal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption.