MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

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Resistance to thyroid hormone (RTH) is an inherited disease linked to mutations in the beta T3 receptor gene and characterized clinically by the resistance of peripheral and pituitary tissues to the action of thyroid hormone. Of the over 50 different mutations identified in the ligand binding domain of the beta receptor, several were shown to inhibit normal receptor function by a dominant negative mechanism which is likely to mediate the phenotype of this disease. Recent studies have indicated that this dominant negative effect is most likely mediated by competition of mutant and normal receptor for binding to T3 response elements within various thyroid hormone responsive genes. We have recently shown that natural thyroid hormone response elements (TRE's) show variation in the dominant negative effect compared to previously employed artificial TRE's. These differences appear to explain the diverse clinical features of RTH. We have recently developed a transgenic model of RTH which should be useful in understanding the function of mutant receptors in vivo and in developing new therapies for the disease. Finally, we have developed novel methods to screen for mutations in the receptor to identify mutations rapidly using automated DNA sequencing. All of these advances should be applicable to other dominant genetic diseases.