Thyroid hormone receptors (T3Rs) both repress and activate gene transcription by 
interacting with auxiliary factors denoted corepressors and coactivators. 
Resistance to thyroid hormone (RTH) syndrome in humans is manifested as a 
failure to respond properly to elevated circulating thyroid hormone. RTH 
syndrome has been mapped to T3Rbeta mutations that alter the transcriptional 
properties of the receptor, resulting in a dominant negative phenotype. We 
report here a characterization of a series of RTH mutant T3Rs that exhibit 
unusual interactions with corepressor. Two mutations in receptor helix 11 
(delta430, delta432) greatly enhance the ability of the mutant receptors to bind 
to corepressor. A distinct mutation, V264D, in an 'omega loop' region of the 
receptor, impairs corepressor release but does not fully eliminate the ability 
to recruit coactivator. These mutations reveal novel determinants that regulate 
the interaction of the T3R with important ancillary cofactors, and that are 
disrupted in a human endocrine disease.