title: A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes.
abstract: Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Ek
authors.forename: Sara P
authors.initials: SP
authors.lastname: Hansen
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.forename: Carine
authors.initials: C
authors.lastname: Nicot
authors.forename: Trine W
authors.initials: TW
authors.lastname: Boesgaard
authors.forename: Stepanka
authors.initials: S
authors.lastname: Pruhova
authors.forename: Anders
authors.initials: A
authors.lastname: Johansen
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Knud
authors.initials: K
authors.lastname: Yderstraede
authors.forename: Jeannet
authors.initials: J
authors.lastname: Lauenborg
authors.forename: Marcelina
authors.initials: M
authors.lastname: Parrizas
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Peter
authors.initials: P
authors.lastname: Damm
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005838:Genotype; D006239:Haplotypes; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D051557:Hepatocyte Nuclear Factor 4