Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB
- Mol Cell. 2020 Feb 20;77(4):875-886.e7. doi: 10.1016/j.molcel.2019.11.008.
- 1. Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA; National Institute of General Medical Sciences, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
- 2. Institute of Neuroanatomy & Developmental Biology (INDB), Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
- 3. Center for Neural Science, New York University, New York, NY 10003, USA.
- 4. Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
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.