elF2γ Mutation that Disrupts elF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation

Together with GTP and initiator methionyl-tRNA, translation initiation factor elF2 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 elF2 gamma (encoded by EIF2S3), the core subunit of the heterotrimeric elF2 complex. Biochemical studies of human cells overexpressing the elF2 gamma mutant and of yeast elF2 gamma with the analogous mutation revealed a defect in binding the elF2 beta subunit to elF2 gamma. Consistent with this loss of elF2 integrity, the yeast elF2 gamma mutation impaired translation start codon selection and elF2 function in vivo in a manner that was suppressed by overexpressing elF2 beta. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of elF2 function.