Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-β receptors?

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-β (TRβ) gene. The purpose of this study was to determine whether the clinical phenotypes of RTH can be translated in terms of functional impairment of the corresponding mutant TRβ. Data from 124 subjects with RTH representing 18 different mutant TRβs, showed that serum free T₄ levels correlated with the degree of T₃-binding impairment of the corresponding TRβ in 12 of these mutant TRβs (group I), but not in the remaining 6 (group II). In subjects from both groups studied in detail by the administration of incremental doses of T₃, the degree of thyrotroph resistance to T₃ correlated with the magnitude of endogenous free T₄ elevation at baseline, but did not parallel the resistance of peripheral tissues. In transfection studies, all group I mutant TRβs inhibited positive transactivation by the wild type TRβs to a similar degree in the presence of 1 nmol/L T₃, whereas group II mutant TRβs exerted a weaker inhibition that was not related to their T₃-dependent transactivation when tested alone. Similar results were obtained with negatively regulated reporter genes. It is concluded that the clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T₃ binding impairment and dominant negative potency of mutant TRβs, but the degree of peripheral tissue resistance and related clinical manifestations is limited by putative genetic or environmental factors that modulate the effect of thyroid hormone.