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

Abstract

Background: Although 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 presentation: A 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.

Conclusions: We 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.

Fig. 1

Identification of the IL10RA mutation associated with infantile-onset inflammatory bowel disease (IOIBD). a A c.537G > A mutation at the 3' end of exon 4 of the IL10RA gene in the family of our patient with IOIBD. Arrows indicate site of mutation. Parts of sequences of exon 4 and intron 4 are shown in upper case and lower case, respectively. b RT-PCR analysis for the IL10RA gene in the patient with c.537G > A mutation. Schematic representation of positions of the primers for RT-PCR and the c.537G > A mutation is given in the upper panel. RT-PCR products from the c.537G > A mutation of the IL10RA gene are shown in the lower panel. The expected 216-bp and 495-bp products of the IL10RA exons 4-5 and exons 2-5, respectively, were detected in a healthy control and the patient, while additional shorter products were observed in the patient (bands 3 and 4). c Sequence analysis of RT-PCR products indicated that the c.537G > A mutation caused 2 kinds of splicing variants; an 18 bp deletion of the 3' end of exon 4 and skipping of exon 4 (170 bp)

Fig. 2

Loss of function of the IL-10 receptor. Functional analysis of IL-10 receptor complex was performed by determining signal transducer and activator of transcription 3 (STAT3) phosphorylation using flow cytometry. Peripheral blood mononuclear cells from the patient (right panel) and his father (left panel) were stimulated for 15 minutes with IL-10 (20 ng/mL) or IL-6 (20 ng/mL) or kept unstimulated, and later fixed, permeabilized and stained for phosphorylated STAT3 (pSTAT3), which is downstream of the IL-10 and IL-6 receptor complexes