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

Hum Mutat. 2017 Apr;38(4):409-425. doi: 10.1002/humu.23170.

Martina Skopkova ¹, Friederike Hennig ², Byung-Sik Shin ³, Clesson E Turner ⁴, Daniela Stanikova ¹ ⁵, Katarina Brennerova ⁵, Juraj Stanik ¹ ⁵ ⁶, Ute Fischer ², Lyndal Henden ⁷ ⁸, Ulrich Müller ⁹, Daniela Steinberger ⁹ ¹⁰, Esther Leshinsky-Silver ¹¹ ¹² ¹³, Armand Bottani ¹⁴, Timea Kurdiova ¹, Jozef Ukropec ¹, Olga Nyitrayova ¹⁵, Miriam Kolnikova ¹⁶, Iwar Klimes ¹, Guntram Borck ¹⁷, Melanie Bahlo ⁷ ⁸, Stefan A Haas ¹⁸, Joo-Ran Kim ³, Leda E Lotspeich-Cole ³, Daniela Gasperikova ¹, Thomas E Dever ³, Vera M Kalscheuer ²

Affiliations

1 DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
2 Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
3 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
4 Department of Genetics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
5 First Department of Pediatrics, Medical Faculty of Comenius University, Bratislava, Slovakia.
6 Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, University of Leipzig, Germany.
7 Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
8 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
9 Institut für Humangenetik, Justus-Liebig-Universität Giessen, Giessen, Germany.
10 bio.logis Center for Human Genetics, Frankfurt a. M., Germany.
11 Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
12 Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.
13 Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
14 Service of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland.
15 Cytopathos, Bratislava, Slovakia.
16 Department of Pediatric Neurology, Medical Faculty of Comenius University, Bratislava, Slovakia.
17 Institute of Human Genetics, University of Ulm, Ulm, Germany.
18 Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.

PMID: 28055140 DOI: 10.1002/humu.23170

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.

Keywords

EIF2S3; MEHMO syndrome; XLID; integrated stress response; translation initiation; unfolded-protein response.

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