Novel exonic mutation inducing aberrant splicing in the IL10RA gene and resulting in infantile-onset inflammatory bowel disease: a case report

Abstract

BackgroundAlthough deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia.Case presentationA Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G > A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission.ConclusionsWe describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-016-0424-5) contains supplementary material, which is available to authorized users.

Interleukin 10/ Interleukin-10R Mutations Causing Very Early Onset Inflammatory Bowel Disease

“…22 cases have been reported in East Asia, of which 21 cases showed IL-10RA mutation with only 1 case showing IL-10RB mutation. This is a contrast to the European cases in which IL-10RA and IL-10RB mutations were almost equal [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].…”

“…These patients present with repeated episodes of bloody diarrhea, significant weight loss, growth retardation and recurrent perianal abscesses, fistulas and fissures [29]. Additionally, in patients with IL-10RB mutations which interrupts the binding between IL-10R1 and IL-22, results in the immune defects of the skin and lung epithelium due to IL-22 signal pathway abnormality, leads to folliculitis and refractory pneumonia [13,25].…”

“…Due to poor efficacy of treatment and drug resistance, some patients have undergone bowel resection and ileostomy or colostomy [22]. As a matter of fact that IL-10 has a predominant action on the immune and hematopoetic cells, an attempt has been made to use Allogenic Hematopoetic Stem Cell Transplantation (HSCT) as a curative therapy for patients of VEO-IBD with mutations of IL-10/IL-10R [10,13,17,19,23,25,30]. Though the initial results have supported the curative role of HSCT in VEO-IBD patients with IL-1O/IL-10R mutations, yet its experience is limited because it has been used only in a few number of patients with a short follow-up period.…”

Variants in cardiac GATA genes associated with bicuspid aortic valve

“…Other synonymous variants have been previously related to BAV in a single‐family study . Actually, the amount of studies showing the functional effect of synonymous changes is increasing . There are many potential mechanisms that may explain the biological effect of synonymous changes and their potential impact on multiple steps of gene expression, including their influence on the processing and stability of mRNA, translational dynamics, protein folding, or alterations in a microRNA binding site .…”

“…32 Actually, the amount of studies showing the functional effect of synonymous changes is increasing. [33][34][35] There are many potential mechanisms that may explain the biological effect of synonymous changes and their potential impact on multiple steps of gene expression, including their influence on the processing and stability of mRNA, translational dynamics, protein folding, or alterations in a microRNA binding site. 36,37 The lack of demonstration of the functional importance of all p.Cys274=, p.His302=, and p.Asn458= variants is a main limitation of our study.…”