Somatic mutation of TRβ can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor

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 TR beta 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 TR beta that caused a His to Tyr substitution at codon 435 of TR beta1 corresponding to codon 450 of TR beta2. Interestingly, this mutation occurred in the same codon as two mutations (TR beta H435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TR beta had impaired T-3 binding and T-3-mediated negative regulation. It also blocked the negative regulation by wild-type TR beta2 on glycoprotein hormone a-subunit and TSH beta reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TR beta occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor.