ArticleHuman mutation2017
EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.
Article in Human mutation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 82 citations in OpenAlex.
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- Illness stress-induced transient hyperglycemia in a patient with a novel YIPF5 homozygous missense variant: expanding the phenotype.Hormones (Athens, Greece) · 2024Review
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- The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Expansion of clinical and variant spectrum of EEF2-related neurodevelopmental disorder: Report of two additional cases.American journal of medical genetics. Part A · 2023Article
- SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.Brain : a journal of neurology · 2023Article
- Human Tissues Exhibit Diverse Composition of Translation Machinery.International journal of molecular sciences · 2023Article
- The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?Human genomics · 2023Article
- Expanding the phenotype of the recurrent truncating eIF2γ pathogenic variant p.(Ile465Serfs*4) identified in two brothers with MEHMO syndrome.Clinical case reports · 2022Article
- Altered proteome in translation initiation fidelity defective eIF5Scientific reports · 2022Article
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- Eukaryotic initiation factor-2, gamma subunit, suppresses proliferation and regulates the cell cycle via the MAPK/ERK signaling pathway in acute myeloid leukemia.Journal of cancer research and clinical oncology · 2021Article
- Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.Nature aging · 2021Article
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26 authors at 13 institutions in 6 countries.
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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.
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