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

作者：Abdulkarim Baroj; Nicolino Marc; Igoillo Esteve Mariana; Daures Mathilde; Romero Sophie; Philippi Anne; Senee Valerie; Lopes Miguel; Cunha Daniel A; Harding Heather P; Derbois Celine; Bendelac Nathalie; Hattersley Andrew T; Eizirik Decio L; Ron David; Cnop Miriam; Julier Cecile

来源：Diabetes, 2015, 64(11): 3951-3962.

DOI：10.2337/db15-0477

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.

• 出版日期2015-11
• 单位河北医科大学