Journal
DIABETES
Volume 64, Issue 11, Pages 3951-3962Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db15-0477
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Funding
- European Union
- Actions de Recherche Concertees de la Communaute Francaise
- Fonds National de la Recherche Scientifique (FNRS), Belgium
- Agence Nationale pour la Recherche [ANR-09-GENO-021]
- European Foundation for the Study of Diabetes/JDRF/Novo Nordisk
- Assistance Publique-Hopitaux de Paris Programme Hospitalier de Recherche Clinique (DIAGENE)
- GIS Maladies Rares
- Wellcome Trust [084812/Z/08/Z]
- European Molecular Biology Organization Short-Term Fellowship
- FNRS-FRIA fellowship
- Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, France
- Wellcome Trust [084812/Z/08/Z] Funding Source: Wellcome Trust
- National Institute for Health Research [NF-SI-0611-10219] Funding Source: researchfish
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Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) are associated with pancreatic beta-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2 alpha phosphorylation [CReP]) encoding the regulatory subunit of an eIF2 alpha-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 eIF2 alpha dephosphorylation and results in beta-cell apoptosis. Our findings support the concept that dysregulated eIF2 alpha phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to beta-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.
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