Nature 384, 458 - 460 (05 December 1996); doi:10.1038/384458a0

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

Kazuya Yamagata^*, Hiroto Furuta^*, Naohisa Oda^*, Pamela J. Kaisaki^*, Stephan Menzel^*, Nancy J. Cox^*, Stefan S. Fajans^†, Stefano Signorini^‡, Markus Stoffel^‡ & Graeme I. Bell^*

^* Howard Hughes Medical Institute, and Departments of Biochemistry & Molecular Biology, and Medicine, The University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, Illinois 60637, USA
^† Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
^‡ Laboratory of Metabolic Diseases, Rockefeller University, New York, New York 10021, USA

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 inheritance¹. 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 -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 glucokinase², a key regulator of insulin secretion, and hepatocyte nuclear factor-1 (HNF-1)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 (gene symbol, TCP14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1 expression⁹⁻¹¹.

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