A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes.
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.
Ek
Jakob
J
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark.
Hansen
Sara P
SP
Lajer
Maria
M
Nicot
Carine
C
Boesgaard
Trine W
TW
Pruhova
Stepanka
S
Johansen
Anders
A
Albrechtsen
Anders
A
Yderstraede
Knud
K
Lauenborg
Jeannet
J
Parrizas
Marcelina
M
Boj
Sylvia F
SF
Jørgensen
Torben
T
Borch-Johnsen
Knut
K
Damm
Peter
P
Ferrer
Jorge
J
Lebl
Jan
J
Pedersen
Oluf
O
Hansen
Torben
T
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
D001786:Blood Glucose; D051557:Hepatocyte Nuclear Factor 4