Functional properties of the R154X HNF-4 alpha protein generated by a mutation associated with maturity-onset diabetes of the young, type 1

Mutations in the hepatocyte nuclear factor 4 alpha (HNF-4 alpha) gene are a ssociated with one form of maturity-onset diabetes of tbe young (MODY1). Th e R154X mutation generates a protein lacking the E-domain which is required for normal HNF-4 alpha functions. Since pancreatic beta-cell dysfunction i s a feature of MODY1 patients, we compared the functional properties of the R154X mutant in insulin-secreting pancreatic beta-cells and non-beta-cells , The R154X mutation did not affect nuclear localisation in beta-cells and non-beta-cells. However, it did lead to a greater impairment of HNF-4 alpha function in beta-cells compared to non-beta-cells, including a complete lo ss of transactivation activity and a dominant-negative behaviour. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.