Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4

Diabetes. 1997 Mar;46(3):528-35. doi: 10.2337/diab.46.3.528.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Child
  • Child, Preschool
  • Codon
  • DNA-Binding Proteins / genetics
  • Diabetes Mellitus, Type 2 / genetics*
  • Exons*
  • Female
  • Frameshift Mutation
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Nuclear Family
  • Nuclear Proteins*
  • Pedigree
  • Point Mutation
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Rats
  • Sequence Deletion
  • Sequence Homology, Nucleic Acid
  • Transcription Factors / genetics*


  • Codon
  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Hnf1a protein, rat
  • Hnf1b protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta

Associated data

  • GENBANK/U72612
  • GENBANK/U72613
  • GENBANK/U72614
  • GENBANK/U72615
  • GENBANK/U72616
  • GENBANK/U72617
  • GENBANK/U72618
  • GENBANK/U73499