Cargando…

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

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 phosphory...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713904/
https://www.ncbi.nlm.nih.gov/pubmed/26159176
http://dx.doi.org/10.2337/db15-0477
_version_ 1782410220485476352
author 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
author_facet 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
author_sort Abdulkarim, Baroj
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4713904
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-47139042016-05-01 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 Genetics/Genomes/Proteomics/Metabolomics 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. American Diabetes Association 2015-11 2015-07-09 /pmc/articles/PMC4713904/ /pubmed/26159176 http://dx.doi.org/10.2337/db15-0477 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Genetics/Genomes/Proteomics/Metabolomics
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
A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title_full A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title_fullStr A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title_full_unstemmed A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title_short A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly
title_sort missense mutation in ppp1r15b causes a syndrome including diabetes, short stature, and microcephaly
topic Genetics/Genomes/Proteomics/Metabolomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713904/
https://www.ncbi.nlm.nih.gov/pubmed/26159176
http://dx.doi.org/10.2337/db15-0477
work_keys_str_mv AT abdulkarimbaroj amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT nicolinomarc amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT igoilloestevemariana amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT dauresmathilde amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT romerosophie amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT philippianne amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT seneevalerie amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT lopesmiguel amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT cunhadaniela amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT hardingheatherp amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT derboisceline amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT bendelacnathalie amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT hattersleyandrewt amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT eizirikdeciol amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT rondavid amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT cnopmiriam amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT juliercecile amissensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT abdulkarimbaroj missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT nicolinomarc missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT igoilloestevemariana missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT dauresmathilde missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT romerosophie missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT philippianne missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT seneevalerie missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT lopesmiguel missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT cunhadaniela missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT hardingheatherp missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT derboisceline missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT bendelacnathalie missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT hattersleyandrewt missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT eizirikdeciol missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT rondavid missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT cnopmiriam missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly
AT juliercecile missensemutationinppp1r15bcausesasyndromeincludingdiabetesshortstatureandmicrocephaly