ArticleNucleic acids research2019
MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 31 citations in OpenAlex.
- Translation Initiation Fidelity Defective Mutations in eIF5 and eIF2β Show Distinct Sensitivity to the Sequence Context for Recognition of the UUG Start Codon.Biochemical genetics · 2026Article
- Male germ cell-specific deletion ofZoological research · 2026Article
- eIF2β zinc-binding domain interacts with the eIF2γ subunit through the guanine nucleotide binding interface to promote Met-tRNAiMet binding.Bioscience reports · 2024Article
- Protein translation: biological processes and therapeutic strategies for human diseases.Signal transduction and targeted therapy · 2024Review
- Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder.American journal of human genetics · 2022Article
- Altered proteome in translation initiation fidelity defective eIF5Scientific reports · 2022Article
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- Eukaryotic initiation factor-2, gamma subunit, suppresses proliferation and regulates the cell cycle via the MAPK/ERK signaling pathway in acute myeloid leukemia.Journal of cancer research and clinical oncology · 2021Article
- Profiling of Sexually Dimorphic Genes in Neural Cells to IdentifyFrontiers in cell and developmental biology · 2021Article
- Article
- Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review.Clinical genetics · 2020Article
- Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy.European journal of human genetics : EJHG · 2020Article
- The integrated stress response: From mechanism to disease.Science (New York, N.Y.) · 2020Review
- Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB.Molecular cell · 2020Article
- MRNA Transcription, Translation, and Defects in Developmental Cognitive and Behavioral Disorders.Frontiers in molecular biosciences · 2020Review
- uORF-mediated translational control: recently elucidated mechanisms and implications in cancer.RNA biology · 2019Review
- Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.EBioMedicine · 2019Article
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Authors and funding
3 authors at 2 institutions in 1 country.
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Abstract
The heterotrimeric eukaryotic translation initiation factor (eIF) 2 plays critical roles in delivering initiator Met-tRNAiMet to the 40S ribosomal subunit and in selecting the translation initiation site. Genetic analyses of patients with MEHMO syndrome, an X-linked intellectual disability syndrome, have identified several unique mutations in the EIF2S3 gene that encodes the γ subunit of eIF2. To gain insights into the molecular consequences of MEHMO syndrome mutations on eIF2 function, we generated a yeast model of the human eIF2γ-I259M mutant, previously identified in a patient with MEHMO syndrome. The corresponding eIF2γ-I318M mutation impaired yeast cell growth and derepressed GCN4 expression, an indicator of defective eIF2-GTP-Met-tRNAiMet complex formation, and, likewise, overexpression of human eIF2γ-I259M derepressed ATF4 messenger RNA translation in human cells. The yeast eIF2γ-I318M mutation also increased initiation from near-cognate start codons. Biochemical analyses revealed a defect in Met-tRNAiMet binding to the mutant yeast eIF2 complexes in vivo and in vitro. Overexpression of tRNAiMet restored Met-tRNAiMet binding to eIF2 in vivo and rescued the growth defect in the eIF2γ-I318M strain. Based on these findings and the structure of eIF2, we propose that the I259M mutation impairs Met-tRNAiMet binding, causing altered control of protein synthesis that underlies MEHMO syndrome.
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