ArticleEBioMedicine2019
Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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28 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
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- Translation Initiation Fidelity Defective Mutations in eIF5 and eIF2β Show Distinct Sensitivity to the Sequence Context for Recognition of the UUG Start Codon.Biochemical genetics · 2026Article
- Diagnostic Challenges of Short Stature and Growth Hormone Insufficiency Across Different Genetic Etiologies.Biomedicines · 2025Review
- A Transcriptomic Approach to Sex Differences in Calcific Aortic Valve Stenosis in Patients with a Tricuspid Aortic Valve.CJC open · 2025Article
- Integrated bioinformatics and machine learning algorithms reveal the unfolded protein response pathways and immune infiltration in acute myocardial infarction.Journal of thoracic disease · 2024Article
- Identification of molecular targets and small drug candidates for Huntington's disease via bioinformatics and a network-based screening approach.Journal of cellular and molecular medicine · 2024Article
- Genetic Variations in Hyperinsulinemic Hypoglycemia: Active versus Inactive Mutations.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus.International journal of molecular sciences · 2023Article
- Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.Human molecular genetics · 2023Article
- Syndromic forms of congenital hyperinsulinism.Frontiers in endocrinology · 2023Review
- Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.European journal of endocrinology · 2022Article
- Expanding the phenotype of the recurrent truncating eIF2γ pathogenic variant p.(Ile465Serfs*4) identified in two brothers with MEHMO syndrome.Clinical case reports · 2022Article
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- Case report: Congenital hyperinsulinemia withFrontiers in pediatrics · 2022Article
- Hypoglycaemia Metabolic Gene Panel Testing.Frontiers in endocrinology · 2022Review
- Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease.Frontiers in endocrinology · 2022Review
- Mosaic GLUD1 Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome.Hormone research in paediatrics · 2022Article
- Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.Nature aging · 2021Article
- Clinical and genetic characteristics of patients with congenital hyperinsulinism in 21 non-consanguineous families from Serbia.European journal of pediatrics · 2021Article
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
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Authors and funding
16 authors at 8 institutions in 3 countries.
Funding
Abstract
backgroundThe heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome.
methodsExome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study.
findingsWe report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast.
interpretationOur data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study.
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