Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone

The syndrome of resistance to thyroid hormone is associated with diverse mu tations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we re port three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occur ring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y re ceptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand w ith reduced affinity, such that its functional impairment and dominant nega tive activity manifest at low concentrations of thyroid hormone, but are mo re reversible at higher T-3 concentrations. The degree of functional impair ment of mutant receptors in vitro may correlate with the magnitude of thyro id dysfunction in vivo. Modelling these mutations using the crystal structu re of thyroid hormone receptor beta shows why ligand binding is perturbed a nd why the phenylalanine/tyrosine mutations are more deleterious than cyste ine.