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

Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.A., N.J.S., P.M.Y.), and Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (E.H.O.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institutes of Health, Building 10, Room 8D12, Bethesda, Maryland 20892. E-mail: pauly{at}intra.niddk.nih.gov

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 TRß 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 TRß that caused a His to Tyr substitution at codon 435 of TRß1 corresponding to codon 450 of TRß2. Interestingly, this mutation occurred in the same codon as two mutations (TRßH435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TRß had impaired T₃ binding and T₃-mediated negative regulation. It also blocked the negative regulation by wild-type TRß2 on glycoprotein hormone -subunit and TSHß reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TRß 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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