A NOVEL C-TERMINAL DOMAIN IN THE THYROID-HORMONE RECEPTOR SELECTIVELYMEDIATES THYROID-HORMONE INHIBITION

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients d isplay inappropriate central secretion of thyrotropin-releasing hormon e (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of R TH, which only leads to abnormal pituitary TSH secretion (PRTH), is un clear. In a patient with PRTH, a novel mutation of a conserved arginin e residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced fun ction on stimulatory thyroid hormone response elements found in periph eral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a membe r of the nuclear receptor superfamily that selectively abolishes hormo ne dependent inhibition and localizes a novel C-terminal domain necess ary for this property.