Maturity onset diabetes of the young (MODY) is a heterogeneous subtype of type II diabetes mellitus. To date, five MODY genes have been identified. Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are associated with MODY3. In the present work, we implemented the HNF-1alpha promoter region in the screening of MODY-suspect patients and identified seven variants not detected in control subjects. The family was available for the -119delG variant, and segregration between MODY and the variant is observed. Most of these variants are located in highly conserved regions and may alter HNF-1alpha expression through binding alteration of nuclear factors or other mechanisms. We demonstrate by functional studies that the transcriptional activity of the -283A>C and -218T>C variant promoters were 30% and 70% of the wild type activity, respectively. These data suggest that HNF-1alpha promoter variants could be diabetogenic mutations, and emphasize that the accurate HNF-1alpha expression is important for the maintenance of normal pancreatic beta cell function.
Copyright 2000 Wiley-Liss, Inc.