@article{fae25921327e46f3b2be844cf4722943,
title = "Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB",
abstract = "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-tRNAi 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.",
keywords = "ATF4, CDC123, CHOP, GADD34, ISRIB, MEHMO syndrome, X-linked intellectual disability, eIF2, eIF2B, integrated stress response",
author = "Young-Baird, {Sara K.} and Louren{\c c}o, {Ma{\'i}ra Bertolessi} and Elder, {Megan K.} and Eric Klann and Stefan Liebau and Dever, {Thomas E.}",
note = "Funding Information: We thank Ronald Wek and Bobby Hogg for plasmids and use of instrumentation, Jizhong Zou and Kaari Linask of the NHLBI iPSC Core as well as the NHBLI Flow Cytometry Core for assistance in generating isogenic iPSCs, Vincent Schram and Lynne Holtzclaw of the NICHD Microscopy and Imaging Core for assistance with imaging and immunocytochemistry analysis, and Guntram Borck, Alan Hinnebusch, Jon Lorsch, Nick Guydosh, and members of the Dever, Hinnebusch, Lorsch, and Guydosh labs for helpful discussions. This work was supported by the Intramural Research Program of the NIH , NICHD (T.E.D.) and by grants from the DFG ( DFG LI 2044/4-1 and DFG LI 2044/5-1 to S.L.) and the NIH ( NS034007 , NS047384 , and HD08201 to E.K.). S.K.Y.-B. was supported by a Postdoctoral Research Associate Training (PRAT) fellowship from the NIGMS , award number GM123961 . Funding Information: We thank Ronald Wek and Bobby Hogg for plasmids and use of instrumentation, Jizhong Zou and Kaari Linask of the NHLBI iPSC Core as well as the NHBLI Flow Cytometry Core for assistance in generating isogenic iPSCs, Vincent Schram and Lynne Holtzclaw of the NICHD Microscopy and Imaging Core for assistance with imaging and immunocytochemistry analysis, and Guntram Borck, Alan Hinnebusch, Jon Lorsch, Nick Guydosh, and members of the Dever, Hinnebusch, Lorsch, and Guydosh labs for helpful discussions. This work was supported by the Intramural Research Program of the NIH, NICHD (T.E.D.) and by grants from the DFG (DFG LI 2044/4-1 and DFG LI 2044/5-1 to S.L.) and the NIH (NS034007, NS047384, and HD08201 to E.K.). S.K.Y.-B. was supported by a Postdoctoral Research Associate Training (PRAT) fellowship from the NIGMS, award number GM123961. S.K.Y.-B. and T.E.D. conceived and designed the study, analyzed and interpreted the data, and wrote the manuscript. S.K.Y.-B. acquired the data; S.K.Y.-B. and M.K.E. acquired and M.K.E. and E.K. analyzed the neuronal data. M.B.L. and S.L. conceived, designed, and performed the keratinocyte isolation and iPSC reprogramming. All authors edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019",
year = "2020",
month = feb,
day = "20",
doi = "10.1016/j.molcel.2019.11.008",
language = "English (US)",
volume = "77",
pages = "875--886.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}