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* * * * * * * * * * * * * * * * * * * * MODY: MATURITY-ONSET DIABETESOF THE YOUNG Stefan S. Fajans, MD University of Michigan May 2004 Maturity-Onset Diabetes of the Young (MODY)1975 Definition Type-2 diabetes mellitus in the young  plus Autosomal dominant inheritance * Current Definition of MODY A heterogeneous disorder due to heterozygous monogenic mutations in one of at least 6 different genes Onset of diabetes early in life: childhood, adolescence, young adulthood Autosomal dominant inheritance Primary defect in insulin secretion * Heterozygous Gene Mutations Identified in MODY Name (Year) Gene Chromosome MODY1 (1991) HNF-4a 20q MODY2 (1993) Glucokinase 7p MODY3 (1996) HNF-1a 12q MODY4 (1997) IPF-1 (PDX-1) 13q MODY5 (1997) HNF-1b 17q MODY6 (1999) Neuro-D1 / BETA-2 2q HNF = Hepatocyte nuclear factor IPF = Insulin promoter factor PDX-1 = Pancreatic duodenal homeobox-1 * Homozygous Mutations of MODY-Related Genes Permanent neonatal diabetes (PND) results from homozygous mutations of Glucokinase gene Insulin promoter factor (IPF-1) gene * MODY-Related Proteins [1/4] Glucokinase Expressed in b-cells and liver Catalyzes transfer of phosphate from ATP to glucose, generating glucose-6-phosphate, a rate-limiting step in glucose metabolism “Glucose sensor” in b-cells Facilitates glycogen synthesis in the liver * MODY-Related Proteins [2/4] Liver-enriched transcription factors HNF-1a, HNF-1b, and HNF-4a Expressed in liver and other organs, including pancreatic islets, kidneys and genitalia Part of a network of transcription factors that function together to control expression of multiple genes Regulate expression of the insulin gene, and genes of proteins involved in glucose transport and metabolism, and mitochondrial metabolism * MODY-Related Proteins [3/4] Transcription factor IPF-1 Expressed in pancreatic islets Regulates transcription of a variety of genes, inc