MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE IN MODY AND EARLY-ONSET NIDDM - EVIDENCE FOR A MUTATIONAL HOTSPOT IN EXON-4

We have recently shown that mutations in the gene encoding the transcr iption factor hepatocyte nuclear factor (HNF)-1 alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we re port the exon-intron organization and partial sequence of the human HN F-1 alpha gene. In addition, we have screened the ten exons and flanki ng 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 mere identified in nine of these individuals, suggesting that mutations in the HNF-1 alpha gene are a common cause of diabetes in German subjects with earl y-onset NIDDM and a family history of diabetes. Thus, screening for mu tations in this gene may be indicated in subjects with early-onset NID DM. Interestingly, three of the nine mutations occurred at the same si te in exon 4 with insertion of a C in a polyC tract, centered around c odon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA p olymorphisms in the HNF-1 alpha gene indicated that the Pro291fsinsC m utation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also i dentified the mutation in the HNF-1 alpha gene in the Jutland pedigree , one of the original MODY pedigrees reported in the literature, as be ing a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of th e HNF-1 alpha 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 function.