Nemati Shahram, Teimourian Shahram, Tabrizi Mina, Najafi Mehri, Dara Naghi, Imanzadeh Farid, Ahmadi Mitra, Aghdam Maryam Kazemi, Tavassoli Mohmoud, Rohani Pejman, Madani Seyyed Ramin, de Boer Martin, Kuijpers T W, Roos Dirk
Department of Medical Genetics, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran, Iran.
Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran; Pediatric Infectious Diseases Research Center, Department of Infectious Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Med Genet. 2017 Dec;60(12):643-649. doi: 10.1016/j.ejmg.2017.08.016. Epub 2017 Aug 30.
BACKGROUND & AIM: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants.
With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes.
In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway.
Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies.
与成人炎症性肠病（IBD）相比，具有早期发病表现的患者在潜在分子病理学、病程及对治疗的反应方面具有不同特征。我们对先前报道的作为婴儿期（极早发）IBD重要病因的白细胞介素-10（IL-10）信号通路进行研究，以寻找任何可能的变异。
采用新一代测序技术，我们对15例患有极早发性胃肠道疾病的儿童的IL-10、IL-10受体A（IL-10RA）和IL-10受体B（IL-10RB）基因进行了筛查。此外，我们基于赛默飞世尔免疫缺陷检测板对在IBD发病机制中具有已知作用或导致具有重叠表现的疾病的基因进行了分析。我们仅对在IL-10相关基因中显示变异的病例进行了多项功能分析。
在15例患者中的3例中，我们鉴定出变异，包括IL-10RA中的纯合和杂合突变以及IL-12RB1中的一个新的纯合突变。我们的功能研究表明，与无有害影响的IL-10RA杂合突变相反，纯合突变消除了IL-10信号通路。
我们的研究表明，我们需要将经典诊断方法从功能测定后进行候选基因或基因测序修改为首先进行平行基因组筛查，然后进行功能研究。
