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Submitted on February 22, 2002
Accepted on May 23, 2002
1 Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute and Laboratory of Biochemical Pharmacology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892-4264 USA
* To whom correspondence should be addressed. E-mail: sycheng{at}helix.nih.gov.
Mutations in the thyroid hormone receptor ß gene (TRß) cause resistance to thyroid hormone (RTH). Genetic analyses indicate that phenotypic manifestation of RTH is due to the dominant negative action of mutant TRß. However, the molecular mechanisms underlying the dominant negative action of mutants and how the same mutation results in marked variability of resistance in different tissues in vivo are not clear. Here we used a knock-in mouse (TRßPV mouse) that faithfully reproduces human RTH to address these questions. We demonstrated directly that TRß1 protein was 
3-fold higher than TR
1 in the liver of TRß+/+ mice, but was not detectable in the heart of wild-type and TRßPV mice. The abundance of PV in the liver was TRßPV/PV > TRßPV/+ mice, but not detectable in the heart. TR1 in the liver was 6-fold higher than that in the heart of wild-type and TRßPV mice. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed not only with TR isoforms for binding to thyroid hormone response elements (TRE), but also competed with TR for the retinoid \x receptors in binding to TRE. These competitions led to the inhibition of the thyroid hormone (T3)-positive regulated genes in the liver. In the heart, however, PV was significantly lower and thus could not effectively compete with TR1 for binding to TRE, resulting in activation of the T3-target genes by higher levels of circulating thyroid hormones. These results indicate that in vivo, differential expression of TR isoforms in tissues dictates the dominant negative activity of mutant ß receptor, thereby resulting in variable phenotypic expression in RTH.
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