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_ATP) 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_ATP 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 [Ca²⁺]_i, 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_ATP channels.

中文翻译：

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导致先天性高胰岛素血症的失活 ABCC8 变异的功能特征

先天性高胰岛素血症（CHI；OMIM：256450）的特点是尽管发生严重低血糖，但胰岛素仍持续分泌。最常见的原因是 ATP 结合盒亚家族 C 成员 8 ( ABCC8 ) 和钾内向整流通道亚家族 J 成员 11 ( KCNJ11 ) 基因的变异。它们编码 ATP 敏感钾 (K _ATP ) 通道亚基磺酰脲受体 1 (SUR1) 和内向整流钾通道 (Kir6.2) 蛋白。一名 7 天大的男性婴儿出现频繁的低血糖发作，临床诊断为 CHI，接受三重全外显子组测序，揭示复合杂合ABCC8变异（c.307C>T，p.His103Tyr；和 c.3313_3315del，p .Ile1105del) 被识别。在用野生型和变异质粒转染的人胚肾 293 (HEK293) 和大鼠胰岛素瘤细胞 (INS-1) 中，p.His103Tyr 形成的 K _ATP通道被传递到质膜，而 p.Ile1105del 或双变体 (p .His103Tyr 与 p.Ile1105del 结合）未能被转运至质膜。与野生型通道相比，变体（p.His103Tyr；p.Ile1105del）形成的通道具有升高的基础[Ca ²⁺ ] _i，但对葡萄糖的刺激没有反应。我们的结果提供证据表明，由于 K _ATP通道的运输缺陷和功能障碍，两个ABCC8变体可能与 CHI 有关。