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- Title
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
- Authors
Abdulkarim, Baroj; Nicolino, Marc; Igoillo-Esteve, Mariana; Daures, Mathilde; Romero, Sophie; Philippi, Anne; Senée, Valérie; Lopes, Miguel; Cunha, Daniel A.; Harding, Heather P.; Derbois, Céline; Bendelac, Nathalie; Hattersley, Andrew T.; Eizirik, Décio L.; Ron, David; Cnop, Miriam; Julier, Cécile
- Abstract
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.
- Subjects
MISSENSE mutation; DIABETES; MICROCEPHALY; SHORT stature; ENDOPLASMIC reticulum; PHOSPHORYLATION; PANCREATIC beta cells; DEPHOSPHORYLATION; ESTERASES; GROWTH disorders; GENETIC mutation; RESEARCH funding; SYNDROMES; CRANIOFACIAL abnormalities
- Publication
Diabetes, 2015, Vol 64, Issue 11, p3951
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-0477