A novel Phe75fsdelT mutation in the hepatocyte nuclear factor-4alpha gene in a Danish pedigree with maturity-onset diabetes of the young.

Mutations in 5 different genes [the hepatocyte nuclear factor (HNF)-4alpha), glucokinase, HNF-1alpha, insulin promoter factor-1, and HNF-1beta genes] have been shown to cause maturity onset diabetes of the young (MODY). About 50% of all known MODY in Danish Caucasian MODY probands can be explained by mutations in the HNF-1alpha gene (MODY3). To estimate the prevalence of MODY caused by mutations in the HNF-4alpha gene (MODY1), we screened 10 non-MODY3 probands for mutations in the minimal promoter and the 12 exons of the HNF-4alpha gene. One of the probands had a novel frameshift mutation (Phe75fsdelT) in exon 2 of the HNF-4alpha gene, resulting in a premature termination of translation after 117 amino acids of the messenger RNA encoded by that allele. The mutation cosegregated with diabetes in the pedigree and was not detected in 84 unrelated Danish Caucasian healthy glucose-tolerant control subjects or in 84 type 2 diabetic patients. At the time of examination, 4 of 6 mutation carriers were treated with insulin and 2 with oral hypoglycemic medication. Two mutation carriers had late-diabetic complications. Even though the HNF-4alpha protein is known to be important in the regulation of genes involved in lipid metabolism, carriers of the mutation did not differ from age and sex-matched control subjects, in regard to levels of fasting serum total cholesterol, serum high-density lipoprotein-cholesterol, and serum triglyceride. In conclusion, by screening 10 non-MODY3 probands for mutations in the HNF-4alpha gene, we identified 1 diabetes-associated frameshift mutation (Phe75fsdelT), suggesting that defects in HNF-4alpha are a rare cause of MODY in Denmark.