EIF2S3 mutations associated with Severe X-Linked Intellectual Disability Syndrome MEHMO
- Author(s)
- Skopkova, M; Hennig, F; Shin, BS; Turner, CE; Stanikova, D; Brennerova, K; Stanik, J; Fischer, U; Henden, L; Muller, U; Steinberger, D; Leshinsky-Silver, E; Bottani, A; Kurdiova, T; Ukropec, J; Nyitrayova, O; Kolnikova, M; Klimes, I; Borck, G; Bahlo, M; Haas, SA; Kim, JR; Lotspeich-Cole, LE; Gasperikova, D; Dever, TE; Kalscheuer, VM;
- Details
- Publication Year 2017-01-05,Volume 38,Issue #4,Page 409-425
- Journal Title
- Hum Mutat
- Publication Type
- Journal Article
- 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 gamma 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 eIF2gamma 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.
- Publisher
- Wiley
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 28055140
- Publisher's Version
- https://doi.org/10.1002/humu.23170
- NHMRC Grants
- NHMRC/1102971, NHMRC/1054618,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-04-06 09:27:22
Last Modified: 2017-04-10 10:26:57