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dc.contributor.authorAbdulkarim, Barojen
dc.contributor.authorNicolino, Marcen
dc.contributor.authorIgoillo-Esteve, Marianaen
dc.contributor.authorDaures, Mathildeen
dc.contributor.authorRomero, Sophieen
dc.contributor.authorPhilippi, Anneen
dc.contributor.authorSenée, Valérieen
dc.contributor.authorLopes, Miguelen
dc.contributor.authorCunha, Daniel Aen
dc.contributor.authorHarding, Heatheren
dc.contributor.authorDerbois, Célineen
dc.contributor.authorBendelac, Nathalieen
dc.contributor.authorHattersley, Andrew Ten
dc.contributor.authorEizirik, Décio Len
dc.contributor.authorRon, Daviden
dc.contributor.authorCnop, Miriamen
dc.contributor.authorJulier, Cécileen
dc.date.accessioned2015-07-10T12:44:03Z
dc.date.available2015-07-10T12:44:03Z
dc.date.issued2015-11-01en
dc.identifier.citationDiabetes 2015, 64(11), 3951-3962. doi: 10.2337/db15-0477en
dc.identifier.issn0012-1797
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248889
dc.description.abstractDysregulated 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.
dc.description.sponsorshipThis 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.
dc.languageengen
dc.language.isoenen
dc.publisherAmerican Diabetes Association
dc.subjectAdolescenten
dc.subjectAdulten
dc.subjectDiabetes Mellitusen
dc.subjectFemaleen
dc.subjectGrowth Disordersen
dc.subjectHumansen
dc.subjectMaleen
dc.subjectMicrocephalyen
dc.subjectMutation, Missenseen
dc.subjectProtein Phosphatase 1en
dc.subjectSyndromeen
dc.titleA Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.en
dc.typeArticle
prism.endingPage3962
prism.issueIdentifier11en
prism.publicationDate2015en
prism.publicationNameDiabetesen
prism.startingPage3951
prism.volume64en
dc.rioxxterms.funderWellcome Turst
dc.rioxxterms.funderNIHR
dc.rioxxterms.projectid084812/Z/08/Z
dcterms.dateAccepted2015-06-30en
rioxxterms.versionofrecord10.2337/db15-0477en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-11-01en
dc.contributor.orcidHarding, Heather [0000-0002-7359-7974]
dc.contributor.orcidRon, David [0000-0002-3014-5636]
dc.identifier.eissn1939-327X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (084812/Z/08/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
cam.issuedOnline2015-10-22en
dc.identifier.urlhttp://diabetes.diabetesjournals.org/content/64/11/3951.article-infoen


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