Kyodo Reiko, Takeuchi Ichiro, Narumi Satoshi, Shimizu Hirotaka, Hata Kenichiro, Yoshioka Takako, Tanase-Nakao Kanako, Shimizu Toshiaki, Arai Katsuhiro
Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan; Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.
Clin Immunol. 2022 May;238:109015. doi: 10.1016/j.clim.2022.109015. Epub 2022 Apr 14.
Genetic variants affecting the function of dual oxidase 2 (DUOX2), the catalytic subunit of membrane-bound enzymes that produce hydrogen peroxide, are associated with very early-onset inflammatory bowel disease (VEO-IBD). We report the case of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years. Infliximab treatment was successful but was discontinued due to delayed reaction. At age 7 years, treatment with ustekinumab was started, and remission has been maintained for more than 2 years. Whole-exome sequencing identified compound heterozygous missense DUOX2 variants of unknown significance (p.[R1212H];[F1490Y]). Protein expression in the whole-cell lysate and plasma membrane was lower in F1490Y-DUOX2 than in wild-type (WT)-DUOX2. Hydrogen peroxide generation upon ionomycin stimulation was lower in cells expressing R1212H-DUOX2 and F1490Y-DUOX2 than in those expressing WT-DUOX2. The novel, inherited, biallelic DUOX2 mutations may be molecular risk factors of VEO-IBD.
影响双氧化酶2（DUOX2）功能的基因变异与极早发型炎症性肠病（VEO-IBD）相关，DUOX2是产生过氧化氢的膜结合酶的催化亚基。我们报告了一名1岁男孩的病例，该男孩在出现血便腹泻后被诊断为VEO-IBD。他在4岁时患有全结肠炎和广泛的小肠溃疡性病变。英夫利昔单抗治疗取得成功，但因延迟反应而停药。7岁时开始使用优特克单抗治疗，缓解状态已维持超过2年。全外显子测序确定了意义不明的复合杂合错义DUOX2变异（p.[R1212H];[F1490Y]）。F1490Y-DUOX2在全细胞裂解物和质膜中的蛋白表达低于野生型（WT）-DUOX2。在离子霉素刺激下，表达R1212H-DUOX2和F1490Y-DUOX2的细胞中过氧化氢的生成低于表达WT-DUOX2的细胞。新的、遗传性的双等位基因DUOX2突变可能是VEO-IBD的分子危险因素。
