A NOVEL TR-BETA MUTATION (R383H) IN RESISTANCE TO THYROID-HORMONE SYNDROME PREDOMINANTLY IMPAIRS COREPRESSOR RELEASE AND NEGATIVE TRANSCRIPTIONAL REGULATION

Resistance to thyroid hormone (RTH) is characterized by elevated serum thyroid hormones, failure to suppress pituitary TSH secretion, and va riable T-3 responsiveness in peripheral tissues. The disorder is assoc iated with diverse mutations that cluster within three areas of the th yroid hormone beta (TR beta) receptor. Here, we report a novel RTH mut ation (R383H), which is located in a region not known to harbor natura lly occurring mutations. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wild-type (WT), negative transcriptional regulation of human TSH alpha and TRH promote rs was impaired in either TR beta 1 or TR beta 2 contexts, and WT rece ptor function was dominantly inhibited. T-3-dependent changes in basal transcription with R383H were also impaired: on the TRH promoter, bas al activation by unliganded R383H was not reversed by T-3 to the same extent as WT; similarly transcriptional silencing by an unliganded Gal 4-R383H fusion was not relieved at a T-3 concentration that derepresse d WT. In keeping with this, ligand-dependent corepressor release by R3 83H, either in a protein-protein interaction assay or as a DNA-bound h eterodimer with retinoid X receptor on either positive or negative thy roid hormone response elements, was disproportionately impaired relati ve to its ligand-binding affinity, whereas its T-3-dependent recruitme nt of coactivator was unimpaired. These properties were shared by anot her previously described RTH mutant (R429Q), and in the crystal struct ure of TR alpha the homologous residues interact in a polar invaginati on. Our data indicate a role for these residues in mediating negative transcriptional regulation and facilitating corepressor release and su ggest that predominant impairment of these functions may be the minima l requirements for causation of RTH.