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

2015; American Diabetes Association; Volume: 64; Issue: 11 Linguagem: Inglês

10.2337/db15-0477

1939-327X

Baroj Abdulkarim, Marc Nicolino, Mariana Igoillo‐Esteve, Mathilde Daures, Sophie Romero, Anne Philippi, Valérie Senée, Miguel Lopes, Daniel A. Cunha, Heather P. Harding, Céline Derbois, Nathalie Bendelac, Andrew T. Hattersley, Décio L. Eizirik, David Ron, Miriam Cnop, Cécile Julier,

Autophagy in Disease and Therapy

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.