title: EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.
abstract: 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.
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Skopkova
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Hennig
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Byung-Sik
authors.initials: BS
authors.lastname: Shin
authors.affiliation: Department of Genetics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
authors.forename: Clesson E
authors.initials: CE
authors.lastname: Turner
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.|First Department of Pediatrics, Medical Faculty of Comenius University, Bratislava, Slovakia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stanikova
authors.affiliation: First Department of Pediatrics, Medical Faculty of Comenius University, Bratislava, Slovakia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Brennerova
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.|First Department of Pediatrics, Medical Faculty of Comenius University, Bratislava, Slovakia.|Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, University of Leipzig, Germany.
authors.forename: Juraj
authors.initials: J
authors.lastname: Stanik
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Lyndal
authors.initials: L
authors.lastname: Henden
authors.affiliation: Institut für Humangenetik, Justus-Liebig-Universität Giessen, Giessen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: Institut für Humangenetik, Justus-Liebig-Universität Giessen, Giessen, Germany.|bio.logis Center for Human Genetics, Frankfurt a. M., Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Steinberger
authors.affiliation: Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.|Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.|Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.affiliation: Service of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Timea
authors.initials: T
authors.lastname: Kurdiova
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Ukropec
authors.affiliation: Cytopathos, Bratislava, Slovakia.
authors.forename: Olga
authors.initials: O
authors.lastname: Nyitrayova
authors.affiliation: Department of Pediatric Neurology, Medical Faculty of Comenius University, Bratislava, Slovakia.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kolnikova
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Iwar
authors.initials: I
authors.lastname: Klimes
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joo-Ran
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Leda E
authors.initials: LE
authors.lastname: Lotspeich-Cole
authors.affiliation: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasperikova
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dever
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
mesh_terms: D000595:Amino Acid Sequence; D004827:Epilepsy; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics*; D005192:Family Health; D005260:Female; D005835:Genitalia / Q000002:abnormalities; D006801:Humans; D007006:Hypogonadism; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008831:Microcephaly; D009154:Mutation; D009765:Obesity; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D015852:Eukaryotic Initiation Factor-2
keywords: EIF2S3; MEHMO syndrome; XLID; integrated stress response; translation initiation; unfolded-protein response