Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation

Abstract

Background The 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. Methods Exome 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. Findings We 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. Interpretation Our 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.

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management

“…Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3) Three cases published with variant in EIF2S3 present an unusual dysregulation of glucose fluctuating between diazoxideresponsive HH and postprandial hyperglycemia, along with learning difficulties and hypopituitarism [64].…”

Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review

“…We also compared clinical findings with phenotypes of previously published patients [1][2][3][4]7,8 We therefore propose including EIF2S3 mutation search in the differential diagnosis of such unsolved cases.…”

“…Pathogenic EIF2S3 variants have been linked with different clinical disorders, ranging from a severe neurological phenotype with severe intellectual disability (ID) and extreme microcephaly, usually as part of MEHMO (mental deficiency, epilepsy, hypogenitalism, microcephaly and obesity) syndrome (OMIM 300148), [1][2][3] to a novel phenotype of hypopituitarism with glucose dysregulation and very mild neurological involvement. 4 While severely affected patients present with all clinical features, less affected patients exhibit only a subset of these features. It remains largely Urania Kotzaeridou and Sara K. Young-Baird contributed equally to this study.…”

“…unknown why clinical severity varies between patients and how the pathogenic variants impact eIF2γ function; and it is becoming clear that the EIF2S3 variants map to distinct regions of eIF2γ, suggesting that they may impact different functions of eIF2γ. [1][2][3][4][5][6] 2 | METHODS…”

The Molecular Basis of Congenital Hypopituitarism and Related Disorders

“…These patients usually have a severe intellectual disability, GHD and microcephaly, with a few reports of hypoglycemia. We recently reported a novel EIF2S3 variant, p.P432S, in a pedigree with endocrine deficits including hypopituitarism and a unique form of glucose dysregulation that fluctuates between hyperinsulinemic hypoglycaemia and post-prandial hyperglycemia, with only mild learning difficulties (173). an EIF2S3 mutation, in that the patients do not have severe intellectual disability, microcephaly, epilepsy or obesity, but instead have a much milder phenotype.…”