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

2.50
Hdl Handle:
http://hdl.handle.net/11287/618123
Title:
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
Authors:
Abdulkarim, B.; Nicolino, M.; Igoillo-Esteve, M.; Daures, M.; Romero, S.; Philippi, A.; Senée, V.; Lopes, M.; Cunha, D. A.; Harding, H. P.; Derbois, C.; Bendelac, N.; Hattersley, Andrew T.; Eizirik, D. L.; Ron, D.; Cnop, M.; Julier, C.
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.
Citation:
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. 2015, 64 (11):3951-62 Diabetes
Publisher:
American Diabetes Association
Journal:
Diabetes
Issue Date:
Nov-2015
URI:
http://hdl.handle.net/11287/618123
DOI:
10.2337/db15-0477
PubMed ID:
26159176
Additional Links:
http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26159176
Note:
This article is freely available via the publisher's site - click on the 'Additional Link' above to access the full text.
Type:
Journal Article; Case Report; Research Support, Non-U.S. Gov't
Language:
en
ISSN:
1939-327X
Appears in Collections:
2015 RD&E publications; Diabetes/Endocrine Services

Full metadata record

DC FieldValue Language
dc.contributor.authorAbdulkarim, B.en
dc.contributor.authorNicolino, M.en
dc.contributor.authorIgoillo-Esteve, M.en
dc.contributor.authorDaures, M.en
dc.contributor.authorRomero, S.en
dc.contributor.authorPhilippi, A.en
dc.contributor.authorSenée, V.en
dc.contributor.authorLopes, M.en
dc.contributor.authorCunha, D. A.en
dc.contributor.authorHarding, H. P.en
dc.contributor.authorDerbois, C.en
dc.contributor.authorBendelac, N.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorEizirik, D. L.en
dc.contributor.authorRon, D.en
dc.contributor.authorCnop, M.en
dc.contributor.authorJulier, C.en
dc.date.accessioned2016-08-09T13:48:32Z-
dc.date.available2016-08-09T13:48:32Z-
dc.date.issued2015-11-
dc.identifier.citationA Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. 2015, 64 (11):3951-62 Diabetesen
dc.identifier.issn1939-327X-
dc.identifier.pmid26159176-
dc.identifier.doi10.2337/db15-0477-
dc.identifier.urihttp://hdl.handle.net/11287/618123-
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.en
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26159176en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleA Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.en
dc.typeJournal Articleen
dc.typeCase Reporten
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalDiabetesen
dc.description.noteThis article is freely available via the publisher's site - click on the 'Additional Link' above to access the full text.en
dc.description.funding084812/Wellcome Trust/United Kingdom 084812/Z/08/Z/Wellcome Trust/United Kingdom 098395/Wellcome Trust/United Kingdom 100140/Wellcome Trust/United Kingdomen
dc.type.versionPublisheden

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