Requirement of corepressor binding of thyroid hormone receptor mutants for dominant negative inhibition

Resistance to thyroid hormone (RTH) is mainly caused by dominant negative inhibition of wild type thyroid hormone receptor (TR) function due to mutations in the ligand binding domain of the TR beta. Because no RTH mutant was identified in the hinge region of the TR, the contribution of this region for dominant negative inhibition was explored. In transient transfection assays, the dominant negative activity of a RTH-type mutant (P453X) was abolished by an introduction of a mutation into the hinge region (P214R). Although this hinge mutation did not alter homo- or heterodimerization with retinoid X receptor (RXR), its association with nuclear receptor corepressor (N-CoR) was impaired. These results indicate that association of corepressor with the RTH mutants through the hinge region is crucial for their dominant negative activity.