Neonatal Hypoglycemia, Early-Onset Diabetes and Hypopituitarism Due to the Mutation in EIF2S3 Gene Causing MEHMO Syndrome

Staník, Juraj; Škopková, Martina; Staníková, Daniela; Brennerova, Katarina; Barák, L; Tichá, Ľubica; Hornová, J; Klimeš, I; Gašperíková, Daniela

doi:10.33549/physiolres.933689

Cited by 32 publications

(21 citation statements)

References 18 publications

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“…Table 3 Clinical phenotypes of male patients with EIF2S3 mutations from four separate studies. Clinical phenotypes from previous reports by Borck et al 5 , Moortgat et al 6 , Skopkova et al 7 , Stanik J et al 29 , and from this current study, respectively. Not all unique additional features listed under each study were present in every patient described; each male within the study had various combinations of these features.…”

Section: Declaration Of Interestssupporting

confidence: 71%

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

Lc¹,

Cb²,

Sk³

et al. 2020

ESPE

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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.

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Section: Declaration Of Interestssupporting

confidence: 71%

“…re-evaluated for the presence of a pancreatic phenotype. Neonatal hypoglycaemia, early onset insulin-dependent diabetes, and variable hypopituitarism have since been noted in some of these patients [29]. However, the cause of the neonatal hypoglycaemia has not, to date, been established.…”

Section: Discussionmentioning

confidence: 99%

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

Lc¹,

Cb²,

Sk³

et al. 2020

ESPE

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“…Previous reports describing EIF2S3 mutations have focussed on ID with microcephaly [[5], [6], [7]]; however, two previously published patients carrying the EIF2S3 frameshift p.Iso465Serfs*4 [7] were re-evaluated for the presence of a pancreatic phenotype. Neonatal hypoglycaemia, early onset insulin-dependent diabetes, and variable hypopituitarism have since been noted in some of these patients [29]. However, the cause of the neonatal hypoglycaemia has not, to date, been established.…”

Section: Discussionmentioning

confidence: 99%

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

Gregory

Ferreira²,

Young‐Baird

et al. 2019

EBioMedicine

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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.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.

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Neonatal Hypoglycemia, Early-Onset Diabetes and Hypopituitarism Due to the Mutation in EIF2S3 Gene Causing MEHMO Syndrome

Cited by 32 publications

References 18 publications

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

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

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

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

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