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

Abstract

Resistance to thyroid hormone (RTH) is a syndrome caused by a mutation in the carboxyl-terminal domain of the thyroid hormone receptor β (TRβ) 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 studies, we demonstrated that Triac has TR isoform- and TRE-specific effects. In this report, we used five natural RTH mutations of the ligand-binding domain in both TRβ1 and TRβ2 isoforms for the evaluation of the effect of T 3 and Triac on regulation of transcription and binding affinity. We show that Triac has superior activity on negatively and positively regulated promoters and higher binding affinity than T 3 for a majority of TRβ1 and TRβ2 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.