Suzuki Tasuku, Sasahara Yoji, Kikuchi Atsuo, Kakuta Humihiko, Kashiwabara Toshihiko, Ishige Takashi, Nakayama Yoshiko, Tanaka Masanori, Hoshino Akihiro, Kanegane Hirokazu, Abukawa Daiki, Kure Shigeo
Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Miyagi, Japan.
J Clin Immunol. 2017 Jan;37(1):67-79. doi: 10.1007/s10875-016-0339-5. Epub 2016 Oct 17.
Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available.
In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients. Mutations in genes responsible for primary immunodeficiency diseases (PID) and clinical and immunological parameters were evaluated according to disease type.
We identified monogenic mutations in 5 of the 35 patients (14.3 %). We identified compound heterozygous and homozygous splice-site mutations in interleukin-10 receptor A (IL-10RA) in two patients, nonsense mutations in X-linked inhibitor of apoptosis protein (XIAP) in two patients, and a missense mutation in cytochrome b beta chain in one patient. Using assays for protein expression levels, IL-10 signaling, and cytokine production, we confirmed that the mutations resulted in loss of function. For each patient, genotype was significantly associated with clinical findings. We successfully treated a patient with a XIAP mutation by allogeneic cord blood hematopoietic stem cell transplantation, and his symptoms were ameliorated completely.
Targeted sequencing and immunological analysis are useful for screening monogenic disorders and selecting curative therapies in pediatric patients with IBD. The genes responsible for PID are frequently involved in pediatric IBD and play critical roles in normal immune homeostasis in the gastrointestinal tract.
儿童炎症性肠病（IBD）是一种由多种因素引起的异质性疾病。尽管明确诊断需要进行基因和免疫分析，但尚无关于日本人群全面基因研究的报道。
本多中心研究共纳入35例16岁以下的日本IBD患者，其中包括27例6岁以下的极早发型IBD患者。对所有患者进行外显子组和靶向基因panel测序。根据疾病类型评估原发性免疫缺陷病（PID）相关基因的突变以及临床和免疫参数。
我们在35例患者中的5例（14.3%）中鉴定出单基因变异。我们在2例患者中鉴定出白细胞介素10受体A（IL-10RA）的复合杂合和纯合剪接位点变异，在2例患者中鉴定出X连锁凋亡抑制蛋白（XIAP）的无义变异，在1例患者中鉴定出细胞色素bβ链的错义变异。通过蛋白质表达水平、IL-10信号传导和细胞因子产生的检测，我们证实这些变异导致功能丧失。对于每例患者，基因型与临床发现显著相关。我们通过异基因脐血造血干细胞移植成功治疗了1例XIAP变异患者，其症状完全缓解。
靶向测序和免疫分析有助于筛查儿童IBD患者的单基因疾病并选择治愈性治疗方法。PID相关基因经常参与儿童IBD，并在胃肠道正常免疫稳态中起关键作用。
