This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ando, S. Articles by Yen, P. M. Search for Related Content PubMed PubMed Citation Articles by Ando, S. Articles by Yen, P. M.

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.

This article has been cited by other articles:

				S. Mamanasiri, S. Yesil, A. M. Dumitrescu, X.-H. Liao, T. Demir, R. E. Weiss, and S. Refetoff Mosaicism of a Thyroid Hormone Receptor-{beta} Gene Mutation in Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3471 - 3477. [Abstract] [Full Text] [PDF]

				H. Furumoto, H. Ying, G. V. R. Chandramouli, L. Zhao, R. L. Walker, P. S. Meltzer, M. C. Willingham, and S.-Y. Cheng An Unliganded Thyroid Hormone {beta} Receptor Activates the Cyclin D1/Cyclin-Dependent Kinase/Retinoblastoma/E2F Pathway and Induces Pituitary Tumorigenesis Mol. Cell. Biol., January 1, 2005; 25(1): 124 - 135. [Abstract] [Full Text] [PDF]

				Y. Kato, H. Ying, M. C. Willingham, and S.-Y. Cheng A Tumor Suppressor Role for Thyroid Hormone {beta} Receptor in a Mouse Model of Thyroid Carcinogenesis Endocrinology, October 1, 2004; 145(10): 4430 - 4438. [Abstract] [Full Text] [PDF]

				P. Maruvada, N. I. Dmitrieva, J. East-Palmer, and P. M. Yen Cell Cycle-dependent Expression of Thyroid Hormone Receptor-{beta} Is a Mechanism for Variable Hormone Sensitivity Mol. Biol. Cell, April 1, 2004; 15(4): 1895 - 1903. [Abstract] [Full Text] [PDF]

				A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Exp Biol Med, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]