Dysregulation of cellular protein synthesis is linked to a variety of diseases. Mutations in EIF2S3, encoding the γ subunit of the heterotrimeric eukaryotic translation initiation factor eIF2, cause MEHMO syndrome, an X-linked intellectual disability disorder. Here, using patient-derived induced pluripotent stem cells, we show that a mutation at the C terminus of eIF2γ impairs CDC123 promotion of eIF2 complex formation and decreases the level of eIF2-GTP-Met-tRNA_i^Met ternary complexes. This reduction in eIF2 activity results in dysregulation of global and gene-specific protein synthesis and enhances cell death upon stress induction. Addition of the drug ISRIB, an activator of the eIF2 guanine nucleotide exchange factor, rescues the cell growth, translation, and neuronal differentiation defects associated with the EIF2S3 mutation, offering the possibility of therapeutic intervention for MEHMO syndrome.

细胞蛋白质合成的失调与多种疾病有关。EIF2S3 中的突变，编码异三聚体真核翻译起始因子 eIF2 的 γ 亚基，导致 MEHMO 综合征，一种 X 连锁智力障碍疾病。在这里，使用患者来源的诱导多能干细胞，我们表明 eIF2γ C 末端的突变会损害 CDC123 促进 eIF2 复合物形成并降低 eIF2-GTP-Met-tRNA _i ^Met的水平三元配合物。eIF2 活性的这种降低导致整体和基因特异性蛋白质合成的失调，并在应激诱导时增强细胞死亡。添加药物 ISRIB（一种 eIF2 鸟嘌呤核苷酸交换因子的激活剂）可挽救与EIF2S3突变相关的细胞生长、翻译和神经元分化缺陷，为 MEHMO 综合征的治疗干预提供了可能性。