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.
Original language | English |
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Journal | Diabetes |
Volume | 55 |
Issue number | 6 |
Pages (from-to) | 1869-73 |
Number of pages | 5 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - 2006 |
Keywords
- Adult
- Age Factors
- Aged
- Binding Sites
- Blood Glucose
- Body Mass Index
- Diabetes Mellitus, Type 2
- Electrophoretic Mobility Shift Assay
- Female
- Genotype
- Haplotypes
- Hepatocyte Nuclear Factor 4
- Humans
- Male
- Middle Aged
- Mutation
- Pedigree
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Protein Binding
- Sex Factors