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Isoform Variable Action among Thyroid Hormone Receptor Mutants Provides Insight into Pituitary Resistance to Thyroid Hormone

Thyroid Unit Department of Medicine Beth Israel Hospital and Harvard Medical School Boston, Massachusetts 02215

Resistance to thyroid hormone (RTH) is due to mutations in the ß-isoform of the thyroid hormone receptor (TR-ß). The mutant TR interferes with the action of normal TR to cause the clinical syndrome. Selective pituitary resistance to thyroid hormone (PRTH) results in inappropriate TSH secretion and peripheral sensitivity to elevated thyroid hormone levels. Association of the PRTH phenotype with in vitro behavior of the mutant TR has proved elusive. Alternative exon utilization results in two TR-ß isoforms, TR-ß1 and TR-ß2, which differ only in their amino termini. Although the TR-ß1 isoform is ubiquitous, the TR-ß2 isoform is found predominantly in the anterior pituitary and brain. To date, in vitro evaluation of RTH mutations has focused on the TR-ß1 isoform. Site-directed mutagenesis was used to create several PRTH (R338L, R338W, V349M, R429Q, I431T) and generalized RTH (337T, P453H) mutations in both TR-ß isoforms. The ability of mutant TRs to act as dominant negative inhibitors of wild type TR-ß function on positive and negative thyroid hormone response elements (pTREs and nTREs, respectively) was evaluated in transient transfection assays. PRTH mutants had no significant dominant negative activity as TR-ß1 isoforms on pTREs found in peripheral tissues or on nTREs found on genes regulating TSH synthesis. PRTH mutants, in contrast, had strong dominant negative activity on these same nTREs as TR-ß2 isoforms. Cotransfected retinoid X receptor- was required for negative T₃ regulation via the TR-ß1 isoform but was not necessary for negative regulation via the TR-ß2 isoform in CV-1 cells. The differing need for retinoid X receptor cotransfection demonstrates two distinct negative T₃-regulatory pathways, one mediated by the TR-ß1 and the other mediated by TR-ß2. The selective effect of PRTH mutations on the TR-ß2 isoform found in the hypothalamus and pituitary vs. the TR-ß1 isoform found in peripheral tissues suggests a molecular mechanism for the PRTH disorder.

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