Broadening the phenotypic spectrum and physiological insights related to EIF2S3 variants

Stephanie Moortgat, Isabelle Manfroid, Hélène Pendeville, Stephen Freeman, Jordane Bourdouxhe, Valérie Benoit, Ahmad Merhi, Christophe Philippe, Laurence Faivre, Isabelle Maystadt

    Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)827-834
    Nombre de pages8
    journalHuman Mutation
    Volume42
    Numéro de publication7
    Les DOIs
    Etat de la publicationPublié - juil. 2021

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