Novel Compound Heterozygote Mutation in IL10RA in a Patient With Very Early-Onset Inflammatory Bowel Disease

错义突变 复合杂合度 突变 外显子组测序 生物 突变体 炎症性肠病 移码突变 杂合子优势 遗传学 分子生物学 医学 基因 疾病 病理 等位基因
作者
Seak Hee Oh,Young Hoon Sung,Inki Kim,Chan Kyu Sim,Jeong Hoon Lee,Minkyung Baek,Chan‐Gi Pack,Chaok Seok,Eul‐Ju Seo,Myeong Sup Lee,Kyung Mo Kim
出处
期刊:Inflammatory Bowel Diseases [Oxford University Press]
卷期号:25 (3): 498-509 被引量:6
标识
DOI:10.1093/ibd/izy353
摘要

Very early-onset inflammatory bowel disease (VEO-IBD) is often associated with monogenetic disorders. IL-10RA deficiency is one of the major causal mutations in VEO-IBD. Here, we aimed to identify the causal mutation associated with severe IBD in a 1-year-old patient, validate the pathogenicity of the mutation, and characterize the mutant protein. To identify the causal mutation, targeted exome sequencing (ES) was performed using the genomic DNA from the patient. To validate the pathogenicity, IL-10RA functional tests were performed using the patient’s peripheral blood mononuclear cells (PBMCs). Additionally, flow cytometry analysis, confocal microscopy on overexpressed green fluorescent protein–fused mutants, and computational analysis on the structures of IL-10RA proteins were performed. We identified a novel compound heterozygote mutation p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of the patient. The missense variant p.Tyr91Cys was previously identified but not functionally tested, and a frameshift variant, p.Pro146Alafs*40, is novel and nonfunctional. PBMCs from the patient showed defective signal transducer and activator of transcription 3 activation. The p.Tyr91Cys mutant protein failed to properly localize on the plasma membrane. The p.Tyr91Cys mutation seems to disrupt the hydrophobic core structure surrounding the tyrosine 91 residue, causing structural instability. Targeted ES and linkage analysis identified novel compound heterozygous mutations p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of a child with severe VEO-IBD. p.Tyr91Cys proteins were functionally defective in IL-10RA signaling and failed to properly localize on the plasma membrane, probably due to its structural instability.

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