Aims/hypothesis: Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1alpha (HNF-1alpha) diabetes.
Methods: Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1alpha were also investigated.
Results: Three new mutations [G415R, R272C and A site of the promoter (+ 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50% of the activity of wild-type HNF-1alpha. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42-75% more activity than the wild-type sequence.
Conclusion/interpretation: Mutations in the HNF-1alpha gene may affect the normal islet function by different molecular mechanisms.