Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome due to hyposensitivity of tissues to thyroid hormones, characterized by elevated serum thyroid hormones and goiter with normal or increased serum TSH. RTH has been associated with mutations in the beta isoform of the TH receptor (TRbeta). Transgenic mouse models of RTH have brought new insights about the syndrome. Absence of TRbeta expression in TRbeta knockout mice led to partial resistance of the thyrotrophs, which was not present in TR alpha knockout mice. However, alpha and beta knockout animals have complete resistance to TH administration and very high serum TSH and thyroid hormones concentrations. Human TRbeta mutants expressed in mouse tissues recapitulated several manifestations of the syndrome. Pituitary or heart specific expression of the TRbeta mutants induced a decrease in thyroid hormone effects on these tissues and resistance to thyroid hormone administration. We also learned from transgenic models that resistance at hypothalamic TRH neurons, in addition to resistance at thyrotropes, is required to generate the increment in serum thyroid hormones. Knockout mice for the coactivator SRC-1 also showed thyrotroph resistance, suggesting that other proteins involved in thyroid hormones genomic actions may be the cause of RTH in humans. Therefore, transgenic models provided in vivo proof that mutants TRbeta exert their dominant negative effect upon all normal isoforms of TR leading to RTH. Further studies using genetic manipulation in mice are expected to bring new information that will help to understand the heterogeneity of clinical presentation in patients with RTH.
Thyroid; TSH; Thyroid hormones; Hormonal resistance; Hormone receptors
