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

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

Diabetes (New York, N.Y.), 2015-11, Vol.64 (11), p.3951-3962 [Periódico revisado por pares]

United States: American Diabetes Association

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Título:
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
Autor: 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
Assuntos: Adolescent ; Adult ; Amino acids ; Apoptosis ; Binding sites ; Cells ; Diabetes ; Diabetes Mellitus - genetics ; Female ; Genetics/Genomes/Proteomics/Metabolomics ; Growth Disorders - genetics ; Humans ; Life Sciences ; Male ; Microcephaly - genetics ; Mutation ; Mutation, Missense ; Phosphorylation ; Protein Phosphatase 1 - genetics ; Syndrome
É parte de: Diabetes (New York, N.Y.), 2015-11, Vol.64 (11), p.3951-3962
Notas: ObjectType-Case Study-3
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-4
content type line 23
ObjectType-Report-2
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PMCID: PMC4713904
B.A., M.N., M.C., and C.J. contributed equally to this work.
Descrição: 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.
Editor: United States: American Diabetes Association
Idioma: Inglês

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

United States: American Diabetes Association

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