Somatic mutation of TR beta 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 suppre ssed by thyroid hormone. The mechanism for this defect in negative regulati on of TSH secretion is not known. To investigate the possibility of a somat ic 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 doma in of TR beta that caused a His to Tyr substitution at codon 435 of TR beta 1 corresponding to codon 450 of TR beta2. Interestingly, this mutation occu rred in the same codon as two mutations (TR beta H435L and H435Q) previousl y 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 re gulation. It also blocked the negative regulation by wild-type TR beta2 on glycoprotein hormone a-subunit and TSH beta reporter genes in cotransfectio n studies. Our results demonstrate that somatic mutation of TR beta occurre d in a TSHoma and was probably responsible for the defect in negative regul ation of TSH by thyroid hormone in the tumor.