Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone
M. Gurnell et al., Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone, ENDOCRINOL, 140(12), 1999, pp. 5901-5906
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.