R127W-HNF-4 alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1

Aims/hypothesis. Mutations in the hepatocyte nuclear factor (HNF)-4 alpha g ene cause the type 1 form of maturity-onset diabetes of the young (MODY1). The R127W mutation is a missense mutation located in the T-box region of HN F-4 alpha that was first identified in a Japanese family with MODY. We have examined the functional properties of this mutation in order to clarify th e molecular basis of MODY1. Methods. The intracellular localisation, DNA bi nding ability, transactivation activity and functional synergism with the c oactivator CREB-binding protein (CBP) of R127W-HNF-4 alpha were investigate d. Results. The nuclear import and functional synergy with CBP of R127W-HNF -4 alpha were normal. The DNA binding ability of the mutant was decreased a s was its transcriptional activation of the HNF-1 alpha and L-type pyruvate kinase (PKL) genes, Conclusion/interpretation. The R127W mutation seems to be a loss-of-function mutation.