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

✍ Scribed by François Godart; Christine Bellanné-Chantelot; Séverine Clauin; Claudia Gragnoli; Amar Abderrahmani; Hélène Blanché; Philippe Boutin; Jean Claude Chèvre; Philippe Froguel; Bernard Bailleul

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 410 KB
• Volume: 15
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/(sici)1098-1004(200002)15:2<173::aid-humu6>3.0.co;2-w

✦ Synopsis

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-1a (HNF-1a) gene are associated with MODY3. In the present work, we implemented the HNF-1a 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-1a 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-1a promoter variants could be diabetogenic mutations, and emphasize that the accurate HNF-1a expression is important for the maintenance of normal pancreatic b cell function.