A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
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Authors
Abdulkarim, Baroj
Nicolino, Marc
Igoillo-Esteve, Mariana
Daures, Mathilde
Romero, Sophie
Philippi, Anne
Senée, Valérie
Lopes, Miguel
Cunha, Daniel A
Derbois, Céline
Bendelac, Nathalie
Hattersley, Andrew T
Eizirik, Décio L
Cnop, Miriam
Julier, Cécile
Publication Date
2015-11-01Journal Title
Diabetes
ISSN
0012-1797
Publisher
American Diabetes Association
Volume
64
Issue
11
Pages
3951-3962
Language
English
Type
Article
Metadata
Show full item recordCitation
Abdulkarim, B., Nicolino, M., Igoillo-Esteve, M., Daures, M., Romero, S., Philippi, A., Senée, V., et al. (2015). A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.. Diabetes, 64 (11), 3951-3962. https://doi.org/10.2337/db15-0477
Abstract
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.
Keywords
Adolescent, Adult, Diabetes Mellitus, Female, Growth Disorders, Humans, Male, Microcephaly, Mutation, Missense, Protein Phosphatase 1, Syndrome
Sponsorship
This work was supported by the European Union 7th Framework Programme (project BetaBat), the Actions de Recherche Concertées de la Communauté Française, and Fonds National de la Recherche Scientifique (FNRS), Belgium, and by grants from the Agence Nationale pour la Recherche (ANR-09-GENO-021), the European Foundation for the Study of Diabetes/JDRF/Novo Nordisk, the Assistance Publique-Hôpitaux de Paris Programme Hospitalier de Recherche Clinique (DIAGENE), the GIS Maladies Rares, and the Wellcome Trust (084812/Z/08/Z). A.T.H. is a Wellcome Trust and National Institute for Health Research senior investigator, and D.R. is a Wellcome Trust Principal Research Fellow. B.A. was supported by an European Molecular Biology Organization Short-Term Fellowship and an FNRS-FRIA fellowship. M.I.-E. is a scientific collaborator of the FNRS. M.D. was supported by a doctoral fellowship from the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche, France.
Funder references
Wellcome Trust (084812/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.2337/db15-0477
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248889
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