Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.

中文翻译：

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EIF2B1 的从头突变影响 eIF2 信号传导导致新生儿/早发性糖尿病和短暂性肝功能障碍


永久性新生儿糖尿病 (PNDM) 是由 β 细胞数量减少或 β 细胞功能受损引起的。了解这种疾病的遗传基础凸显了基本的 β 细胞机制。我们对 44 名 PNDM 患者及其未受影响的父母进行了三重基因组测序，以确定致病的新变异。对 188 名 2 岁前诊断为糖尿病但未进行基因诊断的患者进行了复制研究。 EIF2B1（编码 eIF2B 复合体 α 亚基）是至少三名患者中唯一具有新的从头变异（全部错义）的基因。复制研究又发现了两名患有新发 EIF2B1 变异的患者。除了患有糖尿病外，五名患者中有四人在儿童时期患有肝炎样发作。发现 EIF2B1 从头突变映射到相同的蛋白质表面。我们认为这些变异使得 eIF2B 复合物对 eIF2 磷酸化不敏感，eIF2 磷酸化在应激条件下发生并触发应激反应基因的表达。 eIF2B 无法感知 eIF2 磷酸化可能会导致未折叠蛋白反应不受调节和细胞死亡。我们的结果证实 EIF2B1 新生突变是永久性糖尿病和肝功能障碍的新原因。这些发现证实了细胞应激调节对 β 细胞的重要性，并强调了 EIF2B1 在该途径中的基本作用。