Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Human mutation, 2017-04, Vol.38 (4), p.409-425

Ort / Verlag

United States: Hindawi Limited

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. We connected the X‐linked EIF2S3 gene with MEHMO (intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome. EIF2S3 encodes the gamma subunit of the eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the integrated stress response (ISR). Functional assays in yeast and human cells showed that the identified mutations have a deleterious effect on eIF2 gamma function. Our findings contribute to the increasing list of disorders caused by dysregulation of protein synthesis.