Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1 alpha (TCF1) promoter region in MODY patients

Maturity onset diabetes of the young (MODY) is a heterogeneous subtype of t ype II diabetes mellitus. To date, five MODY genes have been identified. Mu tations in the hepatocyte nuclear factor-1 alpha factor-1 alpha (HNF-1 alph a) gene are associated with MODY3. In the present work, we implemented the HNF-1 alpha promoter region in the screening of MODY-suspect patients and i dentified seven variants not detected in control subjects. The family was a vailable for the -119delG variant, and segregration between MODY and the va riant is observed. Most of these variants are located in highly conserved r egions and may alter HNF-1 alpha expression through binding alteration of n uclear factors or other mechanisms. We demonstrate by functional studies th at the transcriptional activity of the -283A>C and -218T>C variant promoter s were 30% and 70% of the wild type activity, respectively. These data sugg est that HNF-1 alpha promoter variants could be diabetogenic mutations, and emphasize that the accurate HNF-1 alpha expression is important for the ma intenance of normal pancreatic beta cell function. Hum Mutat 15:173-180, 20 00. (C) 2000 Wiley-Liss, Inc.