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 NURSA Molecule Pages Link Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, H. Articles by Cheng, S.-y. Search for Related Content PubMed PubMed Citation Articles by Suzuki, H. Articles by Cheng, S.-y.

Compensatory Role of Thyroid Hormone Receptor (TR)1 in Resistance to Thyroid Hormone: Study in Mice with a Targeted Mutation in the TRß Gene and Deficient in TR1

Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264

Address all correspondence and requests for reprints to: Dr. Sheue-yann Cheng, Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor ß (TRß) gene. Almost all RTH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TR1 isoform in maintaining the normal functions of thyroid hormone (T₃) in these patients. To understand the role of TR1 in the manifestation of RTH, we compared the phenotypes of mice with a targeted dominantly negative mutant TRß (TRßPV) with or without TR1. TRßPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR1 in TRßPV mice, and severe impairment of postnatal growth was manifested in TRßPV mice deficient in TR1. Furthermore, abnormal expression patterns of T₃-target genes in TRßPV mice were altered by the lack of TR1. These results demonstrate that the lack of TR1 exacerbates the manifestation of RTH in TRßPV mice. Therefore, TR1 could play a compensatory role in mediating the functions of T₃ in heterozygous patients with RTH. This compensatory role may be especially crucial for postnatal growth.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

This article has been cited by other articles:

				C. S. Kim, H. Ying, M. C. Willingham, and S.-y. Cheng The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer Carcinogenesis, May 1, 2007; 28(5): 932 - 939. [Abstract] [Full Text] [PDF]

				Genetically Modified Animals in Endocrinology Endocr. Rev., December 1, 2005; 26(7): 985 - 993. [Abstract] [Full Text] [PDF]

				P. J. O'Shea, J. H. D. Bassett, S. Sriskantharajah, H. Ying, S.-y. Cheng, and G. R. Williams Contrasting Skeletal Phenotypes in Mice with an Identical Mutation Targeted to Thyroid Hormone Receptor {alpha}1 or {beta} Mol. Endocrinol., December 1, 2005; 19(12): 3045 - 3059. [Abstract] [Full Text] [PDF]

				H. Ying, F. Furuya, M. C. Willingham, J. Xu, B. W. O'Malley, and S.-y. Cheng Dual Functions of the Steroid Hormone Receptor Coactivator 3 in Modulating Resistance to Thyroid Hormone Mol. Cell. Biol., September 1, 2005; 25(17): 7687 - 7695. [Abstract] [Full Text] [PDF]

				T. M. Ortiga-Carvalho, K. Hashimoto, C. C. Pazos-Moura, D. Geenen, R. Cohen, R. M. Lang, and F. E. Wondisford Thyroid Hormone Resistance in the Heart: Role of the Thyroid Hormone Receptor {beta} Isoform Endocrinology, April 1, 2004; 145(4): 1625 - 1633. [Abstract] [Full Text] [PDF]