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EIF2S3 Mutations Associated with Severe X‐Linked Intellectual Disability Syndrome MEHMO
Author(s) -
Skopkova Martina,
Hennig Friederike,
Shin ByungSik,
Turner Clesson E.,
Stanikova Daniela,
Brennerova Katarina,
Stanik Juraj,
Fischer Ute,
Henden Lyndal,
Müller Ulrich,
Steinberger Daniela,
LeshinskySilver Esther,
Bottani Armand,
Kurdiova Timea,
Ukropec Jozef,
Nyitrayova Olga,
Kolnikova Miriam,
Klimes Iwar,
Borck Guntram,
Bahlo Melanie,
Haas Stefan A.,
Kim JooRan,
LotspeichCole Leda E.,
Gasperikova Daniela,
Dever Thomas E.,
Kalscheuer Vera M.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23170
Subject(s) - missense mutation , frameshift mutation , biology , genetics , intellectual disability , microcephaly , mutation , phenotype , gene
Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded‐protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X‐linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C‐terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms.