Molecular Diagnosis and Characterization of Thyroid Hormone Resistance Syndromes

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Abstract
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-erbAβ thyroid hormone receptor gene result in variable clinical presentations. These mutations are dominant negative in that the mutant receptors inhibit the function of normal β-receptor (from one allele) and normal α-receptor (from two alleles). Several mutant c-erbAβ 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 Bereu patients, display the clinical (phenotypic) results of total absence of β-receptor and homozygous expression of a dominant negative mutant β-receptor, respectively. Further clinical and molecular studies of GRTH should lead to greater insights of the nature of thyroid hormone action in man.

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