Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that 
mediate the biological activities of thyroid hormone (T3). Two THR genes (A and 
B), located on different chromosomes, yield four T3-binding isoforms with highly 
conserved sequences in the DNA- and ligand-binding domains. Mutations of THRB 
cause a human genetic disease, thyroid hormone resistance syndrome (RTH). 
Comprehensive genomic profiling unveiled the contribution of novel 
change-of-function mutations of TRbeta to the pathogenesis of RTH. In addition, 
abnormalities associated with mutations of the THRA gene have been uncovered 
recently. The phenotypic manifestations of mutated THRB and THRA genes are 
distinct, indicating isoform-dependent actions of TR mutants in vivo. Therefore, 
mutant TRs provide a new paradigm to understand the molecular basis of receptor 
disease.