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

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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 percent of patients with NIDDM may have this form of diabetes mellitus [2,3]. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-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-1 alpha (HNF-1 alpha) [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-4 alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1 alpha expression [9-11].

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