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A suppressor locus for MODY3-diabetes
Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036084/ https://www.ncbi.nlm.nih.gov/pubmed/27667715 http://dx.doi.org/10.1038/srep33087 |
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author | Garcia-Gonzalez, Miguel A. Carette, Claire Bagattin, Alessia Chiral, Magali Makinistoglu, Munevver Parla Garbay, Serge Prévost, Géraldine Madaras, Cécile Hérault, Yann Leibovici, Michel Pontoglio, Marco |
author_facet | Garcia-Gonzalez, Miguel A. Carette, Claire Bagattin, Alessia Chiral, Magali Makinistoglu, Munevver Parla Garbay, Serge Prévost, Géraldine Madaras, Cécile Hérault, Yann Leibovici, Michel Pontoglio, Marco |
author_sort | Garcia-Gonzalez, Miguel A. |
collection | PubMed |
description | Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency. |
format | Online Article Text |
id | pubmed-5036084 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50360842016-09-30 A suppressor locus for MODY3-diabetes Garcia-Gonzalez, Miguel A. Carette, Claire Bagattin, Alessia Chiral, Magali Makinistoglu, Munevver Parla Garbay, Serge Prévost, Géraldine Madaras, Cécile Hérault, Yann Leibovici, Michel Pontoglio, Marco Sci Rep Article Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency. Nature Publishing Group 2016-09-26 /pmc/articles/PMC5036084/ /pubmed/27667715 http://dx.doi.org/10.1038/srep33087 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Garcia-Gonzalez, Miguel A. Carette, Claire Bagattin, Alessia Chiral, Magali Makinistoglu, Munevver Parla Garbay, Serge Prévost, Géraldine Madaras, Cécile Hérault, Yann Leibovici, Michel Pontoglio, Marco A suppressor locus for MODY3-diabetes |
title | A suppressor locus for MODY3-diabetes |
title_full | A suppressor locus for MODY3-diabetes |
title_fullStr | A suppressor locus for MODY3-diabetes |
title_full_unstemmed | A suppressor locus for MODY3-diabetes |
title_short | A suppressor locus for MODY3-diabetes |
title_sort | suppressor locus for mody3-diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036084/ https://www.ncbi.nlm.nih.gov/pubmed/27667715 http://dx.doi.org/10.1038/srep33087 |
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