Wang Ping, Liao Hong, Wang Quyou, Xie Hanbing, Xu Bocheng, Xiang Qinqin, Wang He, Yang Mei, Liu Shanling
Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
Clin Genet. 2024 May;105(5):549-554. doi: 10.1111/cge.14484. Epub 2024 Jan 15.
Congenital hyperinsulinism (CHI; OMIM: 256450) is characterized by persistent insulin secretion despite severe hypoglycemia. The most common causes are variants in the ATP-binding cassette subfamily C member 8(ABCC8) and potassium inwardly-rectifying channel subfamily J member 11(KCNJ11) genes. These encode ATP-sensitive potassium (K) channel subunit sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) proteins. A 7-day-old male infant presented with frequent hypoglycemic episodes and was clinically diagnosed with CHI, underwent trio-whole-exome sequencing, revealing compound heterozygous ABCC8 variants (c.307C>T, p.His103Tyr; and c.3313_3315del, p.Ile1105del) were identified. In human embryonic kidney 293 (HEK293) and rat insulinoma cells (INS-1) transfected with wild-type and variant plasmids, K channels formed by p.His103Tyr were delivered to the plasma membrane, whereas p.Ile1105del or double variants (p.His103Tyr coupled with p.Ile1105del) failed to be transported to the plasma membrane. Compared to wild-type channels, the channels formed by the variants (p.His103Tyr; p.Ile1105del) had elevated basal [Ca], but did not respond to stimulation by glucose. Our results provide evidence that the two ABCC8 variants may be related to CHI owing to defective trafficking and dysfunction of K channels.
先天性高胰岛素血症（CHI；OMIM：256450）的特征是尽管存在严重低血糖，但胰岛素仍持续分泌。最常见的病因是ATP结合盒亚家族C成员8（ABCC8）和内向整流钾通道亚家族J成员11（KCNJ11）基因的变异。这些基因编码ATP敏感性钾（K）通道亚基磺脲类受体1（SUR1）和内向整流钾通道（Kir6.2）蛋白。一名7天大的男婴出现频繁低血糖发作，临床诊断为CHI，接受了三联全外显子测序，结果显示鉴定出复合杂合ABCC8变异（c.307C>T，p.His103Tyr；以及c.3313_3315del，p.Ile1105del）。在转染了野生型和变异体质粒的人胚肾293（HEK293）细胞和大鼠胰岛素瘤细胞（INS-1）中，由p.His103Tyr形成的K通道被转运到质膜，而p.Ile1105del或双重变异体（p.His103Tyr与p.Ile1105del结合）未能被转运到质膜。与野生型通道相比，由变异体（p.His103Tyr；p.Ile1105del）形成的通道基础[Ca]升高，但对葡萄糖刺激无反应。我们的结果提供了证据，表明这两个ABCC8变异体可能由于K通道的转运缺陷和功能功能障碍而与CHI相关。
