Molecular diagnosis and characterization of thyroid hormone resistance syndromes.

The genetic basis of generalized resistance to thyroid hormones (GRTH) is now well understood. In the majority of patients, diverse mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene result in variable clinical presentations. These mutations are dominant negative in that the mutant receptors inhibit the function of normal beta-receptor (from one allele) and normal alpha-receptor (from two alleles). Several mutant c-erbA beta receptors have been cloned and synthesized in vitro; these receptors display a wide range of T3-binding affinities from only a two-fold reduction to no detectable T3-binding activity. Recent transfection studies with T3-regulated reporter genes and these mutant receptors have confirmed the dominant negative function of the mutations in patients with GRTH. Two unique patients, the Refetoff and Bercu patients, display the clinical (phenotypic) results of total absence of beta-receptor and homozygous expression of a dominant negative mutant beta-receptor, respectively. Further clinical and molecular studies of GRTH should lead to greater insights of the nature of thyroid hormone action in man.