EIF2γ Mutation that Disrupts eIF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation

Guntram Borck*, Byung Sik Shin, Barbara Stiller, Aviva Mimouni-Bloch, Holger Thiele, Joo Ran Kim, Meghna Thakur, Cindy Skinner, Lara Aschenbach, Pola Smirin-Yosef, Adi Har-Zahav, Gudrun Nürnberg, Janine Altmüller, Peter Frommolt, Kay Hofmann, Osnat Konen, Peter Nürnberg, Arnold Munnich, Charles E. Schwartz, Doron GothelfLaurence Colleaux, Thomas E. Dever, Christian Kubisch, Lina Basel-Vanagaite

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function.

Original languageEnglish
Pages (from-to)641-646
Number of pages6
JournalMolecular Cell
Issue number4
StatePublished - 30 Nov 2012


FundersFunder number
Israeli Ministry of Health Chief Scientist Foundation3-4963
Israeli Science Foundation09/558
South Carolina Department of Disabilities and Special Needs
National Institutes of Health
National Institute of Child Health and Human DevelopmentZIAHD001010
Deutsche Forschungsgemeinschaft
Fondation de France
Centre National de la Recherche Scientifique


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