title: Mutations in the hepatocyte nuclear factor-1alpha 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.
authors.affiliation: Howard Hughes Medical Institute, The University of Chicago, Illinois 60637, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: N
authors.initials: N
authors.lastname: Oda
authors.forename: P J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: S
authors.initials: S
authors.lastname: Menzel
authors.forename: H
authors.initials: H
authors.lastname: Furuta
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: L
authors.initials: L
authors.lastname: Southam
authors.forename: R D
authors.initials: RD
authors.lastname: Cox
authors.forename: G M
authors.initials: GM
authors.lastname: Lathrop
authors.forename: V V
authors.initials: VV
authors.lastname: Boriraj
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Y
authors.initials: Y
authors.lastname: Oda
authors.forename: H
authors.initials: H
authors.lastname: Yano
authors.forename: M M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Nishigori
authors.forename: J
authors.initials: J
authors.lastname: Takeda
authors.forename: S S
authors.initials: SS
authors.lastname: Fajans
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: N
authors.initials: N
authors.lastname: Iwasaki
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: K S
authors.initials: KS
authors.lastname: Polonsky
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
mesh_terms: D000818:Animals; D002881:Chromosomes, Human, Pair 12; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D010375:Pedigree; D051381:Rats; D015183:Restriction Mapping; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta