The Thyroid Hormone Receptors: Molecular Basis of Thyroid Hormone Resistance

Abstract

Major progress has been achieved in the mechanism of action of thyroid hormones thanks to the identification of the T₃ receptor as the product of the proto-oncogene c-erbA. Recognition of subsets of receptors with and without T₃-binding properties and of the interaction of different receptors with each other leads to new insights in cell regulation and development. In thyroid hormone resistance, distinct mutations in the T₃-binding domain of thyroid hormone receptor (TR)β have been identified in unrelated families. No correlation between the type of mutation and tissue resistance has been established. Mutant TRs bind to thyroid hormone response elements (TREs) on both negative or positive T₃-controlled genes. Subjects with heterozygous TRβ gene deletion are not affected, supporting the hypothesis that mutant TRs act through a dominant negative effect. In generalized thyroid hormone resistance, mutated TRβ may interfere through competition for TREs and/or formation of inactive dimers. Finally, deficiency in T₃ receptor auxiliary protein or other accessory proteins or competition between mutant and normal TRs for these factors is not excluded.