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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2015
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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 |
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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 |
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