Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1)

THE disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance 1 . It has been estimated that 2–5% of patients with NIDDM may have this form of diabetes mellitus 2,3 . Clinical studies have shown that predia-betic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic β-cell dysfunction rather than insulin resistance is the primary defect in this disorder 4,5 . Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 ( MODY1 ) 6 , 7 ( MODY2 ) 2 and 12 ( MODY3 } 7 , with MODY2 and MODY3 being allelic with the genes encoding glucokinase 2 , a key regulator of insulin secretion, and hepatocyte nuclear factor-1α (HNF-1α) 8 , a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4α (gene symbol, TCP14 ), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1α expression 9–11 .