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

Mutations in 5 different genes [the hepatocyte nuclear factor (HNF)-4 alpha ), glucokinase, HNF-1 alpha, insulin promoter factor-1, and HNF-1 beta gene s] have been shown to cause maturity onset diabetes of the young (MODY). Ab out 50% of all known MODY in Danish Caucasian MODY probands can be explaine d by mutations in the HNF-1 alpha gene (MODY3). To estimate the prevalence of MODY caused by mutations in the HNF-4 alpha gene (MODY1), we screened 10 non-MODY3 probands for mutations in the minimal promoter and the 12 exons of the HNF-4 alpha gene. One of the probands had a novel frameshift mutatio n (Phe75fsdelT) in exon 2 of the HNF-4 alpha gene, resulting in a premature termination of translation after 117 amino acids of the messenger RNA enco ded by that allele. The mutation cosegregated with diabetes in the pedigree and was not detected in 84 unrelated Danish Caucasian healthy glucose-tole rant control subjects or in 84 type 2 diabetic patients. At the time of exa mination, 4 of 6 mutation carriers were treated with insulin and 2 with ora l hypoglycemic medication. Two mutation carriers had late-diabetic complica tions. Even though the HNF-4 alpha 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 leve ls of fasting serum total cholesterol, serum high-density lipoprotein-chole sterol, and serum triglyceride. In conclusion, by screening 10 non-MODY3 pr obands for mutations in the HNF-4 alpha gene, we identified I diabetes-asso ciated frameshift mutation (Phe75fsdelT), suggesting that defects in HNP-4 alpha are a rare cause of MODY in Denmark.