Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear 
thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are 
transcription factors that act by altering patterns of gene expression. 
Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in 
the TR beta gene. Biochemically, the syndrome is defined by elevated circulating 
levels of free thyroid hormones due to reduced target tissue responsiveness and 
normal, or elevated, levels of thyroid-stimulating hormone (TSH). This 
"inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, 
where the pituitary secretion of TSH is suppressed. Patients with RTH usually 
present with goiter and an euthyroid or mildly hypothyroid metabolic state. 
Thus, pituitary resistance results in hypersecretion of TSH, which compensates, 
at least in part, for hormone resistance in peripheral tissues. Despite this 
compensation, clinical effects of RTH can include short stature, delayed bone 
maturation, hyperactivity, learning disabilities, and hearing defects, as well 
as variable features of hyper- and hypothyroidism. With the exception of a 
single sibship, which harbored a deletion of the entire coding sequence of the 
TR beta gene and a recessive pattern of inheritance, all other cases of RTH have 
been inherited in an autosomal dominant manner or have been de novo heterozygous 
mutations of the TR beta gene. The dominant pattern of inheritance is explained 
by the functional properties of the mutant receptors which act in a dominant 
negative manner to block the activity of normal TR alpha and TR beta receptors. 
Now that a large number of different RTH mutations have been identified, it is 
striking that the mutations are clustered within restricted domains in the 
carboxyterminal region of the receptor. Mutations in these regions have been 
shown to preserve critical receptor functions such as dimerization and DNA 
binding, while inactivating other activites such as T3 binding and 
transcriptional activation. The examination of patients with RTH and their 
mutated receptors has provided important insights into the mechanisms of thyroid 
hormone action, the structure-function relationship of the receptors, and the 
molecular mechanisms of dominant negative activity.