MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

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Generalized thyroid hormone resistance is a disorder of thyroid hormone action characterized by elevated free thyroid hormones and TSH, as well as inappropriate clinical and biochemical signs of euthyroidism or hypothyroidism. Using restriction fragment length polymorphism, we initially linked this disorder to one of the two known thyroid hormone receptor genes, c-erbA-beta on chromosome 3. Subsequently we have shown in several families that this disease is caused by mutations in the ligand binding domain of the beta receptor. In each family characterized there have been unique defects all of which have resulted in nonconservative changes in amino acids that have altered the T3 binding properties of the receptor, while causing no apparent change in DNA binding properties. There was a good correlation between decreased T3 binding and decreased transcriptional activity assessed in a cotransfection assay. In addition, all mutations demonstrated a dominant negative effect on the action of normal receptors. These data suggest that decreased binding of T3 prevents a conformational change in the mutant receptor necessary for transcriptional activity. We are currently elucidating the molecular defects in additional families studied at NIH and are attempting to correlate the unique molecular defects with various clinical manifestations of this syndrome. We are also attempting to express high levels of the receptor using various expression systems. Such studies should allow for the first time an elucidation of the physiologic role of the a and b thyroid hormone receptors for mediating thyroid hormone action in man.