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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.

CONTEXT: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. OBJECTIVE, SETTING, AND PARTICIPANTS: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. RESULTS: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. CONCLUSIONS: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published