Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α* Academic Article uri icon

abstract

  • Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4alpha result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4alpha fail to transactivate transcription of HNF-4alpha-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4alpha. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4alpha, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4alpha. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4alpha agonist nutrients and drugs.

author list (cited authors)

  • Hertz, R., Ben-Haim, N., Petrescu, A. D., Kalderon, B., Berman, I., Eldad, N., Schroeder, F., & Bar-Tana, J.

citation count

  • 24

complete list of authors

  • Hertz, Rachel||Ben-Haim, Nadav||Petrescu, Anca D||Kalderon, Bella||Berman, Inna||Eldad, Naama||Schroeder, Friedhelm||Bar-Tana, Jacob

publication date

  • April 2003