@article{a066733c100040f5920377141d614884,
title = "Broadening the phenotypic spectrum and physiological insights related to EIF2S3 variants",
abstract = "Mental deficiency, epilepsy, hypogonadism, microcephaly, and obesity 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-dependent mechanisms.",
keywords = "apoptosis, CRISPR/Cas9, EIF2S3, MEHMO syndrome, zebrafish",
author = "Stephanie Moortgat and Isabelle Manfroid and H{\'e}l{\`e}ne Pendeville and Stephen Freeman and Jordane Bourdouxhe and Val{\'e}rie Benoit and Ahmad Merhi and Christophe Philippe and Laurence Faivre and Isabelle Maystadt",
note = "Funding Information: We thank the patients and their families for their contribution to this study and clinicians for sending patients' samples to this study. This work was supported by “Fonds de Soutien Marguerite‐Marie Delacroix” (to SM) through a doctoral grant. This work was financially and logistically supported by the “Institut de Pathologie et G{\'e}n{\'e}tique.” We thank Ivan Th{\'e}ate and Luc Leroy for their implication in immunohistochemistry studies. C. Dupont and A. VanBael are thanked for their technical support in fibroblast cultures and Trypan Blue staining. S. Ormenese and J.J. Goval are thanked for the imaging of zebrafish using a confocal microscope. Alexandre Pena Zamora was extremely helpful in informatics and logistical support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN‐ITHACA). Funding Information: We thank the patients and their families for their contribution to this study and clinicians for sending patients' samples to this study. This work was supported by ?Fonds de Soutien Marguerite-Marie Delacroix? (to SM) through a doctoral grant. This work was financially and logistically supported by the ?Institut de Pathologie et G?n?tique.? We thank Ivan Th?ate and Luc Leroy for their implication in immunohistochemistry studies. C. Dupont and A. VanBael are thanked for their technical support in fibroblast cultures and Trypan Blue staining. S. Ormenese and J.J. Goval are thanked for the imaging of zebrafish using a confocal microscope. Alexandre Pena Zamora was extremely helpful in informatics and logistical support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",
year = "2021",
month = jul,
doi = "10.1002/humu.24215",
language = "English",
volume = "42",
pages = "827--834",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley & Sons",
number = "7",
}