Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)

Abstract

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% 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% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases 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-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

“…Hepatocyte nuclear factor-1α (HNF1A) MODY is believed to be the commonest form of MODY [2] and results from heterozygous loss-of-function mutations of transcription factor HNF1A (previously known as TCF1) [3,4]. HNF1A is produced in the liver, kidney, intestine and pancreatic islets [5].…”

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

“…To date, mutations have been identified in the genes for hepatocyte nuclear factors (HNF) 4α, 1α, 1β and NeuroD1 (neurogenic differentiation 1) causing MODY1, 3, 5 and 6, respectively, and in the glucokinase and insulin promoting factor (IPF) genes causing MODY2 and 4 [1][2][3][4][5][6]. After the cloning of the HNF-1α (MODY3) gene on chromosome 12 in 1996 [2], more than 150 different mutations in the gene have been reported. The most common mutation is the Pro291fsinsC mutation, which arises in a mutational hot spot of the HNF-1α gene [7].…”

Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

“…The study was approved by the Ethics Committee of University of the Ryukyus School of Medicine and was carried out in accordance with the Declaration of Helsinki as revised in 2000. The 10 exons, flanking introns, and minimal promoter region were screened for mutations by polymerase chain reaction (PCR) amplification and direct sequencing of the PCR products as described previously [8].…”