Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB

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-tRNAiMet 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. [Display omitted] •MEHMO syndrome mutation eIF2γ-I465Sfs∗4 in translation factor eIF2 activates the ISR•eIF2γ mutation disrupts chaperone CDC123 assembly of α subunit into eIF2 complex•MEHMO syndrome mutation impairs differentiation of iPSCs to neurons•ISRIB rescues growth, translation, and neuronal differentiation defects of MEHMO iPSCs Young-Baird et al. report that a translation initiation factor eIF2γ mutation linked to the intellectual disability MEHMO syndrome disrupts eIF2 complex formation, triggers chronic activation of the integrated stress response, and impairs neuronal differentiation. These cellular defects are rescued by the small molecule ISRIB.