Nuclear hormone receptors are hormone-regulated transcription factors that play 
critical roles in chordate development and homeostasis. Aberrant nuclear hormone 
receptors have been implicated as causal agents in a number of endocrine and 
neoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a 
human genetic disease characterized by an impaired physiological response to 
thyroid hormone. RTH is associated with diverse mutations in the thyroid hormone 
receptor beta-gene. The resulting mutant receptors function as dominant 
negatives, interfering with the actions of normal thyroid hormone receptors 
coexpressed in the same cells. We report here that RTH receptors interact 
aberrantly with a newly recognized family of transcriptional corepressors 
variously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor 
interacting protein-13 (RIP-13), silencing mediator for retinoid and thyroid 
hormone receptors (SMRT), and thyroid hormone receptor-associating cofactor 
(TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from 
corepressors in the presence of thyroid hormone. Two of the RTH mutations 
uncouple corepressor dissociation from hormone binding; two additional RTH 
mutants exhibit an unusually strong interaction with corepressor under all 
hormone conditions tested. Finally, artificial mutants that abolish corepressor 
binding abrogate the dominant negative activity of RTH mutants. We suggest that 
an altered corepressor interaction is likely to play a critical role in the 
dominant negative potency of RTH mutants and may contribute to the variable 
phenotype in this disorder.