A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
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Authors
Abdulkarim, B.
Nicolino, M.
Igoillo-Esteve, M.
Daures, M.
Romero, S.
Philippi, A.
Senée, V.
Lopes, M.
Cunha, D. A.
Harding, H. P.
Journal
Diabetes
Type
Journal Article
Case Report
Research Support, Non-U.S. Gov't
Case Report
Research Support, Non-U.S. Gov't
Publisher
American Diabetes Association
Rights
Archived with thanks to Diabetes
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.
Citation
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. 2015, 64 (11):3951-62 Diabetes
Note
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