DO CLINICAL MANIFESTATIONS OF RESISTANCE TO THYROID-HORMONE CORRELATEWITH THE FUNCTIONAL ALTERATION OF THE CORRESPONDING MUTANT THYROID HORMONE-BETA RECEPTORS

Resistance to thyroid hormone (RTH), a syndrome characterized by varia ble tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-beta (TR beta) gene. The purpose of th is study was to determine whether the clinical phenotypes of RTH can b e translated in terms of functional impairment of the corresponding mu tant TR beta. Data from 124 subjects with RTH representing 18 differen t mutant TR beta s, showed that serum free T-4 levels correlated with the degree of T-3-binding impairment of the corresponding TR beta in 1 2 of these mutant TR beta s (group I), but not in the remaining 6 (gro up II). In subjects from both groups studied in detail by the administ ration of incremental doses of T-3, the degree of thyrotroph resistanc e to T-3 correlated with the magnitude of endogenous free T-4 elevatio n at-baseline, but did not parallel the resistance of peripheral tissu es. In transfection studies, all group I mutant TR beta s inhibited po sitive transactivation by the wild type TR beta s to a similar degree in the presence of 1 nmol/L T-3, whereas group II mutant TR beta s exe rted a weaker inhibition that was not related to their T-3-dependent t ransactivation when tested alone. Similar results were obtained with n egatively regulated reporter genes. It is concluded that the clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T-3 binding impairment and dominant negative poten cy of mutant TR beta s, 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.