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.