title: Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4alpha.
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.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
authors.forename: Nadav
authors.initials: N
authors.lastname: Ben-Haim
authors.forename: Anca D
authors.initials: AD
authors.lastname: Petrescu
authors.forename: Bella
authors.initials: B
authors.lastname: Kalderon
authors.forename: Inna
authors.initials: I
authors.lastname: Berman
authors.forename: Naama
authors.initials: N
authors.lastname: Eldad
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D000214:Acyl Coenzyme A / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D014644:Genetic Variation; D006367:HeLa Cells; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007700:Kinetics; D008024:Ligands; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000214:Acyl Coenzyme A; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D008024:Ligands; C403128:MLX protein, human; D010750:Phosphoproteins; D011994:Recombinant Proteins; D014157:Transcription Factors