DIFFERENTIAL SENSITIVITY OF THYROID-HORMONE RECEPTOR ISOFORM HOMODIMERS AND MUTANT HETERODIMERS TO HORMONE-INDUCED DISSOCIATION FROM DEOXYRIBONUCLEIC-ACID - ITS ROLE IN DOMINANT-NEGATIVE

General resistance to thyroid hormone is an inheritable disease with r esistance of peripheral tissues to elevated levels of thyroid hormone. Genetic studies have shown that it is due to interference in the func tions of wild-type thyroid hormone nuclear receptors (wTRs) via the do minant negative effect of mutant TRs (mTRs). The present study compare d the heterodimerization of the two TR isoforms, TR beta 1 and TR alph a 1, with mutant TRs to understand if mTRs had isoform-dependent domin ant negative action. Using electrophoresis gel mobility shift assay, w e have demonstrated that mutant PV, S, ED, and OK form heterodimers wi th wTR alpha 1 and Delta TR beta 1 (in which the A/B domain of wTR bet a 1 has been deleted), on the F2-thyroid hormone response element (TRE ). In the presence of T-3, both home- and heterodimer complexes are di ssociated in a T-3 concentration dependent manner. The ED(50) for Delt a TR beta 1 homodimers was 3-fold higher than that of wTR alpha 1 homo dimers. ED(50)s for Delta TR beta 1/mTR heterodimers were 10- to 40-fo ld higher than the corresponding wTR alpha 1/mTR heterodimers. Mutant ED and OK homodimers were only partially dissociated at the highest T- 3 concentrations used (100 nm), whereas no dissociation could be detec ted for PV and S homodimers, indicating differential sensitivity of th e FB-bound TR dimers to the T-3-induced dissociation. We presented a m odel that indicates the dissociation of any particular TR dimer from F Z is determined bg competition of T-3 for both of its constituent TRs. By transfection assays, we showed that the potency of the dominant ne gative action of PV on TR alpha 1 and TR beta 1 inversely correlated w ith the sensitivity of the appropriate mTR/wTR heterodimer to T-3-indu ced dissociation from F2. The differential dominant negative action of mutants on the two TR isoforms could play an important role in the he terogeneity of tissue-specific manifestations in patients with resista nce to thyroid hormone.