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The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin . It affects about 2 percent of the world's population and treatment of diabetes and its complications are an increasing health-care burden . Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder . Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5 percent of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger [4-6]. MODY genes have been localized to chromosomes 7, 12 and 20 [5,7,8] and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion [1,9]. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinase  which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1 alpha (HNF-1 alpha, which is encoded by the gene TCF1). HNF-1 alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes [10,11] and also functions as a weak transactivator of the rat insulin-I gene .