In vitro effect of Triac on resistance to thyroid hormone receptor mutants: potential basis for therapy

Resistance to thyroid hormone (RTH) is a syndrome caused by a mutation in t he carboxyl-terminal domain of the thyroid hormone receptor beta (TR beta) gene. 3.5,3'-triiodothyroacetic acid (Triac) has been used on an empirical basis to treat RTH but its efficacy is still controversial. In previous stu dies, we demonstrated that Triac has TR isoform- and TRE-specific effects. In this report, we used five natural RTH mutations of the ligand-binding do main in both TR beta1 and TR beta2 isoforms for the evaluation of the effec t of T-3 and Triac on regulation of transcription and binding affinity. We show that Triac has superior activity on negatively and positively regulate d promoters and higher binding affinity than T-3 for a majority of TR beta1 and TR beta2 mutants. However, the difference of transcriptional activity and binding affinity between both ligands is less for RTH mutants than for wild type receptors. These results suggest that Triac could be a potential treatment for RTH patients. (C) 2001 Elsevier Science Ireland Ltd. All righ ts reserved.