Topic
EIF2S3
About: EIF2S3 is a research topic. Over the lifetime, 9 publications have been published within this topic receiving 231 citations. The topic is also known as: EIF2 & EIF2G.
Papers
Slovak Academy of Sciences1, Max Planck Society2, National Institutes of Health3, Walter Reed National Military Medical Center4, Comenius University in Bratislava5, Leipzig University6, Walter and Eliza Hall Institute of Medical Research7, University of Melbourne8, University of Giessen9, Wolfson Medical Center10, Geneva College11, University of Ulm12
TL;DR: It is proposed 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.
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.
78 citations
TL;DR: In situ hybridization indicated that Eif2s3x mRNA was expressed preferentially in specific brain regions including the habenula, anterodorsal thalamic nucleus, hippocampus, hypothalamus, and cerebellum, suggesting that sexually dimorphic gene expression arises as a consequence of sex chromosome complement.
68 citations
TL;DR: Addition of the drug ISRIB, an activator of the eIF2 guanine nucleotide exchange factor, rescues the cell growth, translation, and neuronal differentiation defects associated with the EIF2S3 mutation, offering the possibility of therapeutic intervention for MEHMO syndrome.
38 citations
TL;DR: In this article, the role of eukaryotic translation initiation factor-2 subunit 3 (EIF2S3) in patients with non-small cell lung and colorectal cancer is investigated.
Abstract: The expression of eukaryotic translation initiation factor-2 subunit 3 (EIF2S3) in patients with non-small cell lung and colorectal cancer is lower than that in healthy individuals. However, the functions of EIF2S3 remain unclear, and its study in leukemia has not been reported. The article aims to explore the role of EIF2S3 in AML (acute myeloid leukemia) and its underlying mechanism. Reverse transcription-quantitative PCR was performed to evaluate the expression levels of EIF2S3, and its association with patient prognosis was determined. Inducible HEL-EIF2S3 and HL-60-EIF2S3 cell lines were established by retrovirus infection. Cellular proliferation and the cell cycle were analyzed using Cell Counting Kit-8 and flow cytometric analyses. Tumorigenic ability was evaluated using xenograft nude mouse model. Gene expression profiles were analyzed in HL-60-EIF2S3 cells by next-generation sequencing, and WB analysis was performed to detect the expression of related proteins. The expression of EIF2S3 in patients with AML was lower than that experiencing CR (P = 0.02). Furthermore, EIF2S3 overexpression inhibited cellular proliferation, halted G0/1 to S phase cell cycle progression, and inhibited tumorigenicity (P = 0.015). 479 differentially expressed genes were identified between HL60-EIF2S3 DOX (−) and HL60-EIF2S3 DOX ( +) cells via NGS and several of them involved in MAPK/ERK signaling pathway. The phosphorylation levels of ERK decreased when EIF2S3 was overexpressed (P < 0.050). EIF2S3 overexpression may result in a decrease in cellular proliferation, cell cycle arrest, and tumorigenic inhibition via the MAPK/ERK signaling pathway in AML cells.
9 citations
TL;DR: In this article, a missense variant (c.433A>G, p (Met145Val) was identified in EIF2S3 in a mildly affected patient and studies on zebrafish confirm the pathogenicity of this novel variant and three previously published missense variants.
Abstract: Mental deficiency, epilepsy, hypogonadism, microcephaly and obesity (MEHMO) syndrome is a severe X-linked syndrome caused by pathogenic variants in EIF2S3. The gene encodes the γ subunit of the eukaryotic translation initiation factor-2, eIF2, essential for protein translation. A recurrent frameshift variant is described in severely affected patients while missense variants usually cause a moderate phenotype. We identified a novel missense variant (c.433A>G, p.(Met145Val)) in EIF2S3 in a mildly affected patient. Studies on zebrafish confirm the pathogenicity of this novel variant and three previously published missense variants. CRISPR/Cas9 knockout of eif2s3 in zebrafish embryos recapitulate the human microcephaly and show increased neuronal cell death. Abnormal high glucose levels were identified in mutant embryos, caused by beta cell and pancreatic progenitor deficiency, not related to apoptosis. Additional studies in patient-derived fibroblasts did not reveal apoptosis. Our results provide new insights into disease physiopathology, suggesting tissue-dependant mechanisms. This article is protected by copyright. All rights reserved.
6 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 2 |
| 2020 | 1 |
| 2019 | 2 |
| 2017 | 1 |
| 2016 | 1 |
| 2012 | 1 |