We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1α 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-1α 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-1α 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 polyCtract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1α 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-1α 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-1α 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 β-cell function.
Mutations in the Hepatocyte Nuclear Factor-1α Gene in MODY and Early-Onset NIDDM: Evidence for a Mutational Hotspot in Exon 4
AP, activating protein; bp, base pairs; C/EBP, CCAAT/enhancer binding protein; kb, kilobase pairs; MODY, maturity-onset diabetes of the young; HNF, hepatocyte nuclear factor; NF, nuclear factor; PAC, Pl-derived artificial chromosome; PCR, polymerase chain reaction.
Pamela J Kaisaki, Stephan Menzel, Tom Lindner, Naohisa Oda, Ilona Rjasanowski, Jürgen Sahm, Gustav Meincke, Jan Schulze, Harald Schmechel, Cornelia Petzold, Hellmuth M Ledermann, Günther Sachse, V Vicky Boriraj, Ruth Menzel, Wolfgang Kerner, Robert C Turner, Kazuya Yamagata, Graeme I Bell; Mutations in the Hepatocyte Nuclear Factor-1α Gene in MODY and Early-Onset NIDDM: Evidence for a Mutational Hotspot in Exon 4. Diabetes 1 March 1997; 46 (3): 528–535. https://doi.org/10.2337/diab.46.3.528
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