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Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)–resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and f...

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Autores principales: Montaser, Hossam, Patel, Kashyap A., Balboa, Diego, Ibrahim, Hazem, Lithovius, Väinö, Näätänen, Anna, Chandra, Vikash, Demir, Korcan, Acar, Sezer, Ben-Omran, Tawfeg, Colclough, Kevin, Locke, Jonathan M., Wakeling, Matthew, Lindahl, Maria, Hattersley, Andrew T., Saarimäki-Vire, Jonna, Otonkoski, Timo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610619/
https://www.ncbi.nlm.nih.gov/pubmed/33500254
http://dx.doi.org/10.2337/db20-1174
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author Montaser, Hossam
Patel, Kashyap A.
Balboa, Diego
Ibrahim, Hazem
Lithovius, Väinö
Näätänen, Anna
Chandra, Vikash
Demir, Korcan
Acar, Sezer
Ben-Omran, Tawfeg
Colclough, Kevin
Locke, Jonathan M.
Wakeling, Matthew
Lindahl, Maria
Hattersley, Andrew T.
Saarimäki-Vire, Jonna
Otonkoski, Timo
author_facet Montaser, Hossam
Patel, Kashyap A.
Balboa, Diego
Ibrahim, Hazem
Lithovius, Väinö
Näätänen, Anna
Chandra, Vikash
Demir, Korcan
Acar, Sezer
Ben-Omran, Tawfeg
Colclough, Kevin
Locke, Jonathan M.
Wakeling, Matthew
Lindahl, Maria
Hattersley, Andrew T.
Saarimäki-Vire, Jonna
Otonkoski, Timo
author_sort Montaser, Hossam
collection PubMed
description Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)–resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process.
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spelling pubmed-76106192021-04-15 Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress Montaser, Hossam Patel, Kashyap A. Balboa, Diego Ibrahim, Hazem Lithovius, Väinö Näätänen, Anna Chandra, Vikash Demir, Korcan Acar, Sezer Ben-Omran, Tawfeg Colclough, Kevin Locke, Jonathan M. Wakeling, Matthew Lindahl, Maria Hattersley, Andrew T. Saarimäki-Vire, Jonna Otonkoski, Timo Diabetes Genetics/Genomes/Proteomics/Metabolomics Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)–resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process. American Diabetes Association 2021-04 2021-01-26 /pmc/articles/PMC7610619/ /pubmed/33500254 http://dx.doi.org/10.2337/db20-1174 Text en © 2021 by the American Diabetes Association https://www.diabetesjournals.org/content/licenseReaders 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. More information is available at https://www.diabetesjournals.org/content/license.
spellingShingle Genetics/Genomes/Proteomics/Metabolomics
Montaser, Hossam
Patel, Kashyap A.
Balboa, Diego
Ibrahim, Hazem
Lithovius, Väinö
Näätänen, Anna
Chandra, Vikash
Demir, Korcan
Acar, Sezer
Ben-Omran, Tawfeg
Colclough, Kevin
Locke, Jonathan M.
Wakeling, Matthew
Lindahl, Maria
Hattersley, Andrew T.
Saarimäki-Vire, Jonna
Otonkoski, Timo
Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title_full Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title_fullStr Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title_full_unstemmed Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title_short Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
title_sort loss of manf causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress
topic Genetics/Genomes/Proteomics/Metabolomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610619/
https://www.ncbi.nlm.nih.gov/pubmed/33500254
http://dx.doi.org/10.2337/db20-1174
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