title: Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.
abstract: We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, University of Chicago, Illinois 60637, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: S
authors.initials: S
authors.lastname: Menzel
authors.forename: T
authors.initials: T
authors.lastname: Lindner
authors.forename: N
authors.initials: N
authors.lastname: Oda
authors.forename: I
authors.initials: I
authors.lastname: Rjasanowski
authors.forename: J
authors.initials: J
authors.lastname: Sahm
authors.forename: G
authors.initials: G
authors.lastname: Meincke
authors.forename: J
authors.initials: J
authors.lastname: Schulze
authors.forename: H
authors.initials: H
authors.lastname: Schmechel
authors.forename: C
authors.initials: C
authors.lastname: Petzold
authors.forename: H M
authors.initials: HM
authors.lastname: Ledermann
authors.forename: G
authors.initials: G
authors.lastname: Sachse
authors.forename: V V
authors.initials: VV
authors.lastname: Boriraj
authors.forename: R
authors.initials: R
authors.lastname: Menzel
authors.forename: W
authors.initials: W
authors.lastname: Kerner
authors.forename: R C
authors.initials: RC
authors.lastname: Turner
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003062:Codon; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009679:Nuclear Family; D009687:Nuclear Proteins; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051381:Rats; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D003062:Codon; 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