EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

Timea Kurdiova, Vera M Kalscheuer, Thomas E Dever, Daniela Gasperikova, Leda E Lotspeich-Cole, Joo-Ran Kim, Stefan A Haas, Melanie Bahlo, Guntram Borck, Iwar Klimes, Miriam Kolnikova, Olga Nyitrayova, Jozef Ukropec, Martina Skopkova, Armand Bottani, Esther Leshinsky-Silver, Daniela Steinberger, Ulrich Müller, Lyndal Henden, Ute Fischer, Juraj Stanik, Katarina Brennerova, Daniela Stanikova, Clesson E Turner, Byung-Sik Shin, Friederike Hennig

Journal: Human mutation 2018;38(4):409-425

PMID: 28055140

Free Full Text on PubMed Central View on PubMed

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.

Address: DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.; Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.; Department of Genetics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.; First Department of Pediatrics, Medical Faculty of Comenius University, Bratislava, Slovakia.; Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, University of Leipzig, Germany.; 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.; Institut für Humangenetik, Justus-Liebig-Universität Giessen, Giessen, Germany.; bio.logis Center for Human Genetics, Frankfurt a. M., Germany.; 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.; Service of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland.; Cytopathos, Bratislava, Slovakia.; Department of Pediatric Neurology, Medical Faculty of Comenius University, Bratislava, Slovakia.; Institute of Human Genetics, University of Ulm, Ulm, Germany.; Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.

DOI: 10.1002/humu.23170

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/epilepsy.html

Other Literature Sources:

Molecular Biology Databases:

Subscription / membership required

Full Text Sources:

MeSH Terms: Amino Acid Sequence, Epilepsy, Eukaryotic Initiation Factor-2, Family Health, Female, Genitalia, Humans, Hypogonadism, Intellectual Disability, Male, X-Linked Intellectual Disability, Microcephaly, Mutation, Obesity, Pedigree, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Syndrome