EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO

Martina Skopkova, Friederike Hennig, Byung Sik Shin, Clesson E. Turner, Daniela Stanikova, Katarina Brennerova, Juraj Stanik, Ute Fischer, Lyndal Henden, Ulrich Müller, Daniela Steinberger, Esther Leshinsky-Silver, Armand Bottani, Timea Kurdiova, Jozef Ukropec, Olga Nyitrayova, Miriam Kolnikova, Iwar Klimes, Guntram Borck, Melanie Bahlo & 6 others Stefan A. Haas, Joo Ran Kim, Leda E. Lotspeich-Cole, Daniela Gasperikova*, Thomas E. Dever, Vera M. Kalscheuer

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)409-425
Number of pages17
JournalHuman mutation
Volume38
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017
Externally publishedYes

Keywords

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

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