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A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.

par Abdulkarim, Baroj ;Nicolino, Marc;Igoillo Esteve, Mariana ;Daures, Mathilde;Romero, Sophie;Philippi, Anne;Senée, Valérie;Lopes, Miguel ;Andrade Da Cunha, Daniel ;Harding, Heather P;Derbois, Céline;Bendelac, Nathalie;Hattersley, Andrew T;Eizirik, Decio ;Ron, David;Cnop, Miriam ;Julier, Cécile
Référence Diabetes (New York, N.Y.), 64, 11, page (3951-3962)
Publication Publié, 2015-11

Article révisé par les pairs

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Résumé :

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2α dephosphorylation and results in β-cell apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.