title: Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1alpha (TCF1) promoter region in MODY patients.
abstract: 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.
authors.affiliation: Institut de Biologie de Lille, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Godart
authors.forename: C
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: S
authors.initials: S
authors.lastname: Clauin
authors.forename: C
authors.initials: C
authors.lastname: Gragnoli
authors.forename: A
authors.initials: A
authors.lastname: Abderrahmani
authors.forename: H
authors.initials: H
authors.lastname: Blanché
authors.forename: P
authors.initials: P
authors.lastname: Boutin
authors.forename: J C
authors.initials: JC
authors.lastname: Chèvre
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: B
authors.initials: B
authors.lastname: Bailleul
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D016384:Consensus Sequence / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D009711:Nucleotides / Q000235:genetics*; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D009711:Nucleotides; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA