Inflammatory Bowel Disease 25, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that inflammatory bowel disease-25 (IBD25) is caused by homozygous mutation in the IL10RB gene (123889) on chromosome 21q22.

Another form of early-onset inflammatory bowel disease, IBD28 (613148), is caused by mutation in the IL10RA gene (146933) encoding the IL10R1 protein which, together with the IL10R2 protein encoded by IL10RB, forms the heterotetrameric IL10 (124092) receptor.

For a general description and discussion of genetic heterogeneity of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, see IBD1 (266600).

Clinical Features

Glocker et al. (2009) reported a brother and sister from a consanguineous Turkish family, who presented in the first year of life with cutaneous folliculitis, proctitis, perianal abscesses, enterocutaneous fistulas, and, in the girl, rectovaginal fistula. Both sibs underwent multiple surgical interventions, including bowel resections, colostomy, and ileostomy. The sibs also had recurrent infections, believed to be related to immunosuppressive therapy, including otitis media, bronchitis, pneumonia, purulent gonarthritis, and renal abscess. The boy received an allogeneic hematopoietic stem cell transplant from an unaffected HLA-matched sib; shortly after transplantation, the cutaneous folliculitis and inflammatory anal fistulas resolved, and the patient remained in continuous remission from ileocolitis more than a year later.

Begue et al. (2011) studied a French boy who had onset of perianal lesions and pancolitis with granulomas at 3 months of age. He later developed epidodes of cutaneous folliculitis as well as bronchial infections, and also experienced 1 episode of mastoiditis. The patient's hematopoietic cells and intestinal tissue showed no response to IL10 or IL22 (605330), respectively.

Mapping

Kugathasan et al. (2008) carried out a genomewide association analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. They identified significant association between a SNP at chromosome 21q22, rs2836878 (P = 6.01 x 10(-8); odds ratio = 0.73) and pediatric-onset IBD. This SNP was replicated in an independent replication cohort and the Wellcome Trust Case Control Consortium (2007) CD cohort with similar odds ratios and a combined P value of 4.48 x 10(-12). The 21q22 signal resides in a small region of linkage disequilibrium (LD) that harbors no genes, but the nearest gene is PSMG1 (605296). Kugathasan et al. (2008) observed a modest increase in colonic expression of PSMG1 in IBD cases compared to controls. However, the expression did not vary with either the degree of mucosal inflammation or the carriage of the alleles at the 21q22 locus.

McGovern et al. (2010) combined new data from 2 genomewide association studies of ulcerative colitis involving 266,047 SNPs and performed a metaanalysis with previously published data (Silverberg et al., 2009), thus bringing together a discovery set of 2,693 European UC patients and 6,791 controls. McGovern et al. (2010) confirmed association with UC at rs2836878 (combined p = 1.4 x 10(-8)).

Linkage with the IL10RB Gene

In a consanguineous Turkish family in which a brother and sister had early-onset severe enterocolitis, Glocker et al. (2009) performed genomewide microsatellite mapping and identified markers showing segregation with the phenotype on chromosome 21q; fine mapping narrowed the critical region to a 350-kb interval between D21S1257 and D21S1898.

Molecular Genetics

In a consanguineous Turkish family with early-onset severe enterocolitis, Glocker et al. (2009) sequenced the candidate gene IL10RB (123889) and identified homozygosity for a nonsense mutation in 2 affected sibs (123889.0002). The mutation was detected in heterozygosity in the unaffected parents and 2 unaffected sibs, but was not found in 180 German controls, 70 Turkish controls, or 30 Iranian controls. Glocker et al. (2009) analyzed the IL10RB gene in 90 patients with adult-onset IBD, 45 with Crohn disease and 45 with ulcerative colitis, but found no mutations or other sequence variations.

In a French boy with early-onset inflammatory bowel disease in whom hematopoietic cells showed a lack of response to IL10, Begue et al. (2011) identified homozygosity for a nonsense mutation in the IL10RB gene (123889.0003). His unaffected parents and brother were heterozygous for the mutation.