Somatic Mutation of TR Can Cause a Defect in Negative Regulation of TSH in a TSH-Secreting Pituitary Tumor

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Abstract
In patients with TSH-secreting tumors (TSHomas), serum TSH is poorly suppressed by thyroid hormone. The mechanism for this defect in negative regulation of TSH secretion is not known. To investigate the possibility of a somatic mutation of TR causing this defect, we performed mutational analysis of TRβ by RT-PCR using RNA obtained from five surgically resected TSHomas. In one TSHoma, we identified a somatic mutation in the ligand-binding domain of TRβ that caused a His to Tyr substitution at codon 435 of TRβ1 corresponding to codon 450 of TRβ2. Interestingly, this mutation occurred in the same codon as two mutations (TRβH435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TRβ had impaired T3 binding and T3-mediated negative regulation. It also blocked the negative regulation by wild-type TRβ2 on glycoprotein hormoneα -subunit and TSHβ reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TRβ occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor.

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