The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor-2 (eIF2), a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40S ribosomal subunit. The acronym MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity) was coined by Steinmuller et al (PMID: 9781023) who described a large three-generation family with five affected boys and mapped the disease locus to the short arm of chromosome X. Using chromosome X-exome sequencing, Skopkova et al. (2017) identified a frameshift mutation I465Sfs in EIF2S3 in an affected male in the family reported by Steinmüller et al (1998). Functional assays using a yeast/human (Sc/Hs) chimeric form of eIF2γ in yeast demonstrated the variant impairs eIF2γ function. The same variant was also detected in other 3 unrelated families with typical MEHMO syndrome features in affected males. Sequencing data suggested a founder effect for this variant (PMID: 28055140, 27333055, 29303605). Five missense mutations, which exhibited reduced growth rate and/or impaired translation function in yeast, were also reported in male patients exhibiting either typical features of MEHMO or milder phenotypes with a subset of MEHMO features, supporting clinically variable expressivity of MEHMO in patients with deleterious EIF2S3 variants (PMID: 23063529, 27333055, 30878599, 32799315). The association is seen in 14 probands in 6 publications (PMID: 27333055, 28055140, 23063529, 29303605, 30878599, 32799315). The mechanism for disease is expected to be hemizygous loss of function. All reported female carriers are asymptomatic. Morpholino-based knockdown of the zebrafish EIF2S3 ortholog recapitulates the human microcephaly and short stature phenotype (PMID: 27333055). An EIF2S3 knockdown human pancreatic β cell line showed impaired cell survival and increased caspase activities (PMID: 30878599). In summary, the EIF2S3 /MEHMO syndrome gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This was approved the ClinGen Intellectual Disability Gene Curation Expert Panel on November 11, 2021 (SOP version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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