TY - JOUR
T1 - EIF2γ Mutation that Disrupts eIF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation
AU - Borck, Guntram
AU - Shin, Byung Sik
AU - Stiller, Barbara
AU - Mimouni-Bloch, Aviva
AU - Thiele, Holger
AU - Kim, Joo Ran
AU - Thakur, Meghna
AU - Skinner, Cindy
AU - Aschenbach, Lara
AU - Smirin-Yosef, Pola
AU - Har-Zahav, Adi
AU - Nürnberg, Gudrun
AU - Altmüller, Janine
AU - Frommolt, Peter
AU - Hofmann, Kay
AU - Konen, Osnat
AU - Nürnberg, Peter
AU - Munnich, Arnold
AU - Schwartz, Charles E.
AU - Gothelf, Doron
AU - Colleaux, Laurence
AU - Dever, Thomas E.
AU - Kubisch, Christian
AU - Basel-Vanagaite, Lina
N1 - Funding Information:
We wish to thank the family members for their invaluable participation and cooperation and Fatima Abidi for bioinformatic sequence analyses. This work was supported in part by the Deutsche Forschungsgemeinschaft (G.B.), the intramural research program of the National Institutes of Health (T.E.D.), the Israeli Ministry of Health Chief Scientist foundation (grant No 3-4963) and Israeli Science Foundation (grant No 09/558) (L.B.-V.), and by a grant from the South Carolina Department of Disabilities and Special Needs (C.E.S.). L.C.’s laboratory was supported in part by the Centre National de la Recherche Scientifique and the Fondation de France.
PY - 2012/11/30
Y1 - 2012/11/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870392659&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.09.005
DO - 10.1016/j.molcel.2012.09.005
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C2 - 23063529
AN - SCOPUS:84870392659
SN - 1097-2765
VL - 48
SP - 641
EP - 646
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -