Mechanisms by Which Thyroid Hormone Receptor Mutations Cause Clinical Syndromes of Resistance to Thyroid Hormone

Resistance to thyroid hormone (RTH) is an autosomal dominant disorder that is caused by mutations in the thyroid hormone receptor β (TRβ) gene. The thyroid hormone receptor is a nuclear receptor that acts by binding to DNA to stimulate or repress gene transcription. Mutations that cause RTH are clustered within two regions of the hormone binding domain of the receptor. These mutations reduce thyroid hormone binding in most cases, but preserve the ability of the receptor to dimerize and to bind to DNA. Consequently, the mutant receptors are thought to occupy DNA target sites as inactive complexes that are not capable of activation by hormone. Not only are RTH mutants inactive, but they function in a dominant negative manner to block the access of normal receptors to thyroid hormone responsive genes. The mechanism of dominant negative activity and the relationship of genotype and phenotype remain active areas of investigation.