SPECTRUM OF TRANSCRIPTIONAL, DIMERIZATION, AND DOMINANT-NEGATIVE PROPERTIES OF 20 DIFFERENT MUTANT THYROID-HORMONE BETA-RECEPTORS IN THYROID-HORMONE RESISTANCE SYNDROME

Resistance to thyroid hormone (RTH) is usually dominantly inherited an d characterized by elevated thyroid hormone levels, impaired feedback inhibition of pituitary TSH production, and variable hormonal responsi veness in peripheral tissues. We have identified 20 different mutation s in the thyroid hormone beta-receptor (TR beta) gene in RTH and assay ed mutant receptor properties using the TSH alpha subunit gene promote r or promoters containing three different types of positive thyroid re sponse element (TRE). Dominant negative inhibition of wild type TR bet a action by mutant receptors was also tested. The mutant receptors exh ibited differing transcriptional inhibitory properties and dominant ne gative potential with the TSH alpha promoter that correlated with thei r impaired hormone binding, whereas transactivation and dominant negat ive effects with promoters containing positive TREs varied depending o n their configuration. Heterodimeric mutant receptor-retinoid X recept or (RXR) interactions, either in cultured cells or as TRE-bound comple xes in gel retardation assays, were uniformly preserved, whereas homod imeric receptor interactions could not be detected in vivo, and in vit ro homodimer formation on TREs was variably reduced or absent for some mutant proteins. We correlate these findings with the distribution of receptor mutations that cluster in two areas within the hormone bindi ng domain outside putative dimerization regions and show that artifici al mutations that impaired heterodimerization abrogated dominant negat ive activity. Therefore, we suggest that the dominant negative effect of mutant receptors in the pituitary-thyroid axis generates the charac teristic biochemical abnormality of RTH and that variable resistance i n other tissues may be due to response element -dependent differences in their dominant negative potential.