A suppressor locus for MODY3-diabetes

• Published in: Scientific reports Vol. 6; no. 1; p. 33087
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-09-2016; Nature Publishing Group
• Subjects: 38/22; 38/43; 631/208/2490/1472; 64/60; 692/163/2743/137/773; 82/51; 96/2; Biochemistry, Molecular Biology; Blood glucose; Chromosome 3; Chromosomes; Diabetes; Diabetes mellitus; Fasting; Genetic suppression; Genetics; Genome-wide association studies; Genomes; Humanities and Social Sciences; Insulin; Insulin secretion; Laboratory testing; Life Sciences; multidisciplinary; Science; Secretion; Single-nucleotide polymorphism; Synteny
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep33087

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.