A Mutant Thyroid Hormone Receptor β1 Identified in a Patient with Resistance to Thyroid Hormone Inhibits the Activities of Not Only the Wild-Type TRs, but also Other Nuclear Receptors

Abstract

Although mutations of human thyroid hormone receptor β (hTRβ) have been associated with resistance to thyroid hormone (RTH), the molecular basis by which the mutant TRs cause the various clinical symptoms is unknown. We show here that a mutant TRE β identified in a patient with RTH inhibited the transcriptional activities of, not only the wild-type TRβ, but also other nuclear receptors including retinoid X receptorα (RXRα), vitamin D3 receptor (VDR) and retinoic acid receptor (RARα). We provide evidence that these inhibitions by the mutant TREβ occur by different mechanisms. Namely, the mutant TRβ interferes with VDR and RARα by competition for binding to the corresponding response elements, but the pathway through RXRα is mainly inhibited by squelching of RXRα in solution. These findings suggest that in patients with RTH, not only the T3 responsive genes but also other responsive genes are inhibited by the mutant TRs, which might explain the variety of clinical symptoms in RTH.