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Garcia-Gonzalez MA, Carette C, Bagattin A, et al. A suppressor locus for MODY3-diabetes. Sci Rep. 2016;6:33087doi: 10.1038/srep33087.
Garcia-Gonzalez, M. A., Carette, C., Bagattin, A., Chiral, M., Makinistoglu, M. P., Garbay, S., Prévost, G., Madaras, C., Hérault, Y., Leibovici, M., & Pontoglio, M. (2016). A suppressor locus for MODY3-diabetes. Scientific reports, 633087. https://doi.org/10.1038/srep33087
Garcia-Gonzalez, Miguel A, et al. "A suppressor locus for MODY3-diabetes." Scientific reports vol. 6 (2016): 33087. doi: https://doi.org/10.1038/srep33087
Garcia-Gonzalez MA, Carette C, Bagattin A, Chiral M, Makinistoglu MP, Garbay S, Prévost G, Madaras C, Hérault Y, Leibovici M, Pontoglio M. A suppressor locus for MODY3-diabetes. Sci Rep. 2016 Sep 26;6:33087. doi: 10.1038/srep33087. PMID: 27667715; PMCID: PMC5036084.
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Sci Rep. 2016 Sep 26;6:33087. doi: 10.1038/srep33087.

A suppressor locus for MODY3-diabetes.

Scientific reports

Miguel A Garcia-Gonzalez, Claire Carette, Alessia Bagattin, Magali Chiral, Munevver Parla Makinistoglu, Serge Garbay, Géraldine Prévost, Cécile Madaras, Yann Hérault, Michel Leibovici, Marco Pontoglio

Affiliations

  1. Laboratoire d' Expression Génique, Développement et Maladies (EGDM), Département Développement, Reproduction et Cancer, INSERM U1016, Institut Cochin, Paris, France.
  2. Centre National de la Recherche Scientifique, CNRS UMR7104, Paris, France.
  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France.
  5. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
  6. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.

PMID: 27667715 PMCID: PMC5036084 DOI: 10.1038/srep33087

Abstract

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.

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