Molecular genetics and pathophysiology of thyroid hormone resistance

Resistance to thyroid hormone (RTH) is usually dominantly inherited and associated with diverse mutations in the thyroid hormone receptor (TR) β gene, localizing to three regions (residues 234 to 282, 310 to 353, 429 to 461) in the receptor hormone-binding domain. The mutant receptors are transcrip-tionally impaired owing to reduced ligand binding or coactiva-tor recruitment and also inhibit wild-type receptor action in a dominant negative manner. This dominant negative action of mutant receptors is abrogated by disruption of their binding to DNA, retinoid X receptor, or corepressor, which correlates with the absence of natural mutations in receptor domains mediating these functions. More recently recognized features of RTH include attention-deficit hyperactivity disorder, low body mass index in childhood, and hearing abnormalities. Although both generalized and pituitary RTH are associated with TRβ defects, there is growing evidence that some mutations predispose to the pituitary RTH phenotype, possibly because of their selective dominant negative action in a TRβ2 but not TRβ1 context. Targeted disruption of the mouse TRβ gene recapitulates many features of recessively inherited RTH, but heterozygous mice are normal, confirming that haploinsufficiency at this locus does not result in RTH. The phenotype in TRα mutant mice is quite dissimilar to RTH, suggesting that homologous mutations in TRα1 are unlikely to mediate the human disorder.