Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2015-11, Vol.64 (11), p.3951-3962

Ort / Verlag

United States: American Diabetes Association

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.