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Resistance to Thyroid Hormone Caused by Two Mutant Thyroid Hormone Receptors ß, R243Q and R243W, with Marked Impairment of Function That Cannot Be Explained by Altered in Vitro 3,5,3'-Triiodothyroinine Binding Affinity¹

Departments of Pediatrics (H.Y., J.P., S.R.) and Medicine (Y.H., S.R.), and the J. P. Kennedy, Jr., Mental Retardation Research Center (S.R.), University of Chicago, Chicago, Illinois 60637; and the Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University (Y.H.), Nagoya; and the Department of Geriatrics, Endocrinology, and Metabolism, Shinshu University School of Medicine (A.S.), Matsumoto, Japan

Address all correspondence and requests for reprints to: Samuel Refetoff, M.D., University of Chicago (MC3090), 5841 South Maryland Avenue, Chicago, Illinois 60637-1470.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness to thyroid hormone caused by mutations in the thyroid hormone receptor ß (TRß) gene. Mutant TRßs exhibit variable degrees of impaired T₃ binding resulting in reduced T₃-mediated function. The dominant mode of inheritance is attributed to the ability of mutant TRßs to interfere with the function of the wild-type (WT) TR, a phenomenon known as dominant negative effect (DNE). We recently identified two families with RTH having mutations in amino acid 243 (R243Q and R243W) in whom the mechanism of RTH appears to be distinct from that of other natural TRß mutations. These mutations, which are located in the hinge domain of the TRß, do not significantly alter the binding affinity for T₃, measured in vitro. The present study was undertaken to characterize the properties of these mutant TRßs to understand the molecular basis of the RTH phenotype. Two other mutant TRß producing RTH with mild (320H) and severe (345R) impairment of T₃ binding were studied in parallel. The results demonstrate that TRßs 243Q and 243W could be translocated into the nucleus where they exerted normal ligand-independent repression of positively regulated thyroid hormone response elements. Yet, the addition of 10 nmol/L T₃ failed to normalize the transactivation (16–13% of WT) and revert the DNE exerted by the two TRß mutants. In contrast, at this T₃ concentration, the transactivation function of 320H was significantly higher (50% of WT), and the DNE was completely abolished, in keeping with the mild clinical form of RTH. Formation of 243Q and 243W homodimers on thyroid hormone response elements could not be as readily prevented by T₃ as those formed by the WT and 320H TRßs. These results suggest that the substitution of R243 in TRß produces RTH by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T₃ only after it binds to DNA.

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