Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Thyroid hormone receptors and resistance to thyroid hormone disorders

Nature Reviews Endocrinology volume 10, pages 582–591 (2014)Cite this article

Subjects

Key Points

  • The main isoforms of thyroid hormone receptors, THRα1, THRβ1 and THRβ2, are predominantly responsible for mediating thyroid hormone action, which is critical for normal development, growth and metabolism

  • Patients with mutations in either THRA or THRB have been described and have strikingly different clinical phenotypes known as resistance to thyroid hormone (RTH)α and RTHβ, respectively

  • Patients with RTHβ frequently present with elevated thyroid hormone levels, normal or elevated TSH levels and goitre, which suggests a critical role for THRB in negative-feedback regulation

  • Currently only seven patients with RTHα have been described; these individuals have near-normal levels of thyroid hormones and TSH but display hypothyroidism, delayed growth and constipation

  • Studies of mutations associated with RTH disorders using transgenic mouse models have provided novel insights into the divergent roles of THRA and THRB in physiology

Abstract

Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic–pituitary–thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of thyroid hormone action.
Figure 2: The THRα and THRβ isoforms have considerable homology.
Figure 3: Model of gene regulation by thyroid hormones.
Figure 4: Overview of tissues and homeostatic functions affected in RTHβ.
Figure 5: Overview of tissues and homeostatic functions affected in RTHα.

Similar content being viewed by others

Article 19 May 2022

Layal Chaker, Salman Razvi, … Robin P. Peeters

References

  1. Cheng, S. Y., Leonard, J. L. & Davis, P. J. Molecular aspects of thyroid hormone actions. Endocr. Rev. 31, 139–170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brent, G. A. Mechanisms of thyroid hormone action. J. Clin. Invest. 122, 3035–3043 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chiamolera, M. I. & Wondisford, F. E. Minireview: Thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology 150, 1091–1096 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Nikrodhanond, A. A. et al. Dominant role of thyrotropin-releasing hormone in the hypothalamic–pituitary–thyroid axis. J. Biol. Chem. 281, 5000–5007 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Gereben, B. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr. Rev. 29, 898–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bianco, A. C. Minireview: cracking the metabolic code for thyroid hormone signaling. Endocrinology 152, 3306–3311 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chiamolera, M. I. et al. Fundamentally distinct roles of thyroid hormone receptor isoforms in a thyrotroph cell line are due to differential DNA binding. Mol. Endocrinol. 26, 926–939 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sap, J. et al. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 324, 635–640 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Oetting, A. & Yen, P. M. New insights into thyroid hormone action. Best Pract. Res. Clin. Endocrinol. Metab. 21, 193–208 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Refetoff, S. et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Thyroid 24, 407–409 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shibusawa, N. et al. Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. J. Clin. Invest. 112, 588–597 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ortiga-Carvalho, T. M. et al. Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface. J. Clin. Invest. 115, 2517–2523 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaneshige, M. et al. Mice with a targeted mutation in the thyroid hormone β receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc. Natl Acad. Sci. USA 97, 13209–13214 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferrara, A. M. et al. Homozygous thyroid hormone receptor β-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. J. Clin. Endocrinol. Metab. 97, 1328–1336 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaneshige, M. et al. A targeted dominant negative mutation of the thyroid hormone α1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc. Natl Acad. Sci. USA 98, 15095–15100 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bochukova, E. et al. A mutation in the thyroid hormone receptor α gene. N. Engl. J. Med. 366, 243–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Moran, C. et al. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol. http://dx.doi.org/10.1016/S2213-8587(14)70111-1.

  18. Moran, C. et al. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor α. J. Clin. Endocrinol. Metab. 98, 4254–4261 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. van Mullem, A. et al. Clinical phenotype and mutant TRα1. N. Engl. J. Med. 366, 1451–1453 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Refetoff, S. & Dumitrescu, A. M. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract. Res. Clin. Endocrinol. Metab. 21, 277–305 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Phan, T. Q., Jow, M. M. & Privalsky, M. L. DNA recognition by thyroid hormone and retinoic acid receptors: 3, 4, 5 rule modified. Mol. Cell Endocrinol. 319, 88–98 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Warnmark, A., Treuter, E., Wright, A. P. & Gustafsson, J. A. Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Mol. Endocrinol. 17, 1901–1909 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Figueira, A. C. et al. Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange. Mol. Endocrinol. 25, 15–31 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Chassande, O. et al. Identification of transcripts initiated from an internal promoter in the c-erbA α locus that encode inhibitors of retinoic acid receptor-α and triiodothyronine receptor activities. Mol. Endocrinol. 11, 1278–1290 (1997).

    CAS  PubMed  Google Scholar 

  25. Gauthier, K. et al. Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development. EMBO J. 18, 623–631 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Williams, G. R. Cloning and characterization of two novel thyroid hormone receptor β isoforms. Mol. Cell Biol. 20, 8329–8342 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wallis, K. et al. The thyroid hormone receptor α1 protein is expressed in embryonic postmitotic neurons and persists in most adult neurons. Mol. Endocrinol. 24, 1904–1916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bradley, D. J., Towle, H. C. & Young, W. S. 3rd. Spatial and temporal expression of α- and β-thyroid hormone receptor mRNAs, including the β2-subtype, in the developing mammalian nervous system. J. Neurosci. 12, 2288–2302 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bradley, D. J., Towle, H. C. & Young, W. S. 3rd. α and β thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc. Natl Acad. Sci. USA 91, 439–443 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kilby, M. D. et al. Circulating thyroid hormone concentrations and placental thyroid hormone receptor expression in normal human pregnancy and pregnancy complicated by intrauterine growth restriction (IUGR). J. Clin. Endocrinol. Metab. 83, 2964–2971 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Feng, X., Jiang, Y., Meltzer, P. & Yen, P. M. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. Mol. Endocrinol. 14, 947–955 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Flores-Morales, A. et al. Patterns of liver gene expression governed by TRβ. Mol. Endocrinol. 16, 1257–1268 (2002).

    CAS  PubMed  Google Scholar 

  33. de Araujo, A. S., Martinez, L., de Paula Nicoluci, R., Skaf, M. S. & Polikarpov, I. Structural modeling of high-affinity thyroid receptor-ligand complexes. Eur. Biophys. J. 39, 1523–1536 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Valadares, N. F., Polikarpov, I. & Garratt, R. C. Ligand induced interaction of thyroid hormone receptor β with its coregulators. J. Steroid Biochem. Mol. Biol. 112, 205–212 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Weiss, R. E. et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor α or β genes may be due to a defective cofactor. J. Clin. Endocrinol. Metab. 81, 4196–4203 (1996).

    CAS  PubMed  Google Scholar 

  36. Souza, P. C. et al. Helix 12 dynamics and thyroid hormone receptor activity: experimental and molecular dynamics studies of Ile280 mutants. J. Mol. Biol. 412, 882–893 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Alonso, M. et al. In vivo interaction of steroid receptor coactivator (SRC)-1 and the activation function-2 domain of the thyroid hormone receptor (TR) β in TRβ E457A knock-in and SRC-1 knockout mice. Endocrinology 150, 3927–3934 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lavery, D. N. & McEwan, I. J. Structure and function of steroid receptor AF1 transactivation domains: induction of active conformations. Biochem. J. 391, 449–464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cohen, R. N. et al. The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains. Mol. Endocrinol. 15, 1049–1061 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Hollenberg, A. N., Monden, T. & Wondisford, F. E. Ligand-independent and -dependent functions of thyroid hormone receptor isoforms depend upon their distinct amino termini. J. Biol. Chem. 270, 14274–14280 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Hashimoto, K. et al. Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. J. Biol. Chem. 281, 295–302 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, Y. Y. et al. A mutant thyroid hormone receptor α antagonizes peroxisome proliferator-activated receptor α signaling in vivo and impairs fatty acid oxidation. Endocrinology 148, 1206–1217 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Brent, G. A. et al. Capacity for cooperative binding of thyroid hormone (T3) receptor dimers defines wild type T3 response elements. Mol. Endocrinol. 6, 502–514 (1992).

    CAS  PubMed  Google Scholar 

  44. Ayers, S. et al. Genome-wide binding patterns of thyroid hormone receptor β. PLoS One 9, e81186 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chatonnet, F., Guyot, R., Benoit, G. & Flamant, F. Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells. Proc. Natl Acad. Sci. USA 110, E766–E775 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Astapova, I. et al. The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo. Proc. Natl Acad. Sci. USA 105, 19544–19549 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Feng, W. et al. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280, 1747–1749 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Darimont, B. D. et al. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 12, 3343–3356 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McKenna, N. J. et al. Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J. Steroid Biochem. Mol. Biol. 69, 3–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Shibusawa, N., Hollenberg, A. N. & Wondisford, F. E. Thyroid hormone receptor DNA binding is required for both positive and negative gene regulation. J. Biol. Chem. 278, 732–738 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Sasaki, S. et al. Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin β gene. EMBO J. 18, 5389–5398 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Santos, G. M. et al. Negative regulation of superoxide dismutase-1 promoter by thyroid hormone. Mol. Pharmacol. 70, 793–800 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Weiss, R. E. et al. Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J. 18, 1900–1904 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kamiya, Y. et al. Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone. Endocrinology 144, 4144–4153 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Costa-e-Sousa, R. H., Astapova, I., Ye, F., Wondisford, F. E. & Hollenberg, A. N. The thyroid axis is regulated by NCoR1 via its actions in the pituitary. Endocrinology 153, 5049–5057 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Aninye, I. O., Matsumoto, S., Sidhaye, A. R. & Wondisford, F. E. Circadian regulation of Tshb gene expression by Rev-Erbα (NR1D1) and nuclear corepressor 1 (NCOR1). J. Biol. Chem. 289, 17070–17077 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Treuter, E., Albrektsen, T., Johansson, L., Leers, J. & Gustafsson, J. A. A regulatory role for RIP140 in nuclear receptor activation. Mol. Endocrinol. 12, 864–881 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Ramadoss, P. et al. Novel mechanism of positive versus negative regulation by thyroid hormone receptor β1 (TRβ1) identified by genome-wide profiling of binding sites in mouse liver. J. Biol. Chem. 289, 1313–1328 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Abel, E. D., Ahima, R. S., Boers, M. E., Elmquist, J. K. & Wondisford, F. E. Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. J. Clin. Invest. 107, 1017–1023 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gauthier, K. et al. Genetic analysis reveals different functions for the products of the thyroid hormone receptor α locus. Mol. Cell Biol. 21, 4748–4760 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Macchia, P. E. et al. Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α. Proc. Natl Acad. Sci. USA 98, 349–354 (2001).

    CAS  PubMed  Google Scholar 

  62. Gothe, S. et al. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev. 13, 1329–1341 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pazos-Moura, C. et al. Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor. Circ. Res. 86, 700–706 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Ono, S. et al. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J. Clin. Endocrinol. Metab. 73, 990–994 (1991).

    Article  CAS  PubMed  Google Scholar 

  65. Usala, S. J. et al. A homozygous deletion in the c-erbA β thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol. Endocrinol. 5, 327–335 (1991).

    Article  CAS  PubMed  Google Scholar 

  66. Takeda, K., Sakurai, A., DeGroot, L. J. & Refetoff, S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-β gene. J. Clin. Endocrinol. Metab. 74, 49–55 (1992).

    CAS  PubMed  Google Scholar 

  67. van Mullem, A. A. et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: consequences of LT4 treatment. J. Clin. Endocrinol. Metab. 98, 3029–3038 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Forrest, D., Erway, L. C., Ng, L., Altschuler, R. & Curran, T. Thyroid hormone receptor β is essential for development of auditory function. Nat. Genet. 13, 354–357 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Forrest, D. & Vennstrom, B. Functions of thyroid hormone receptors in mice. Thyroid 10, 41–52 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Abel, E. D. et al. Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system. J. Clin. Invest. 104, 291–300 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dettling, J. et al. Autonomous functions of murine thyroid hormone receptor TRα and TRβ in cochlear hair cells. Mol. Cell Endocrinol. 382, 26–37 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Portella, A. C. et al. Thyroid hormone receptor β mutation causes severe impairment of cerebellar development. Mol. Cell Neurosci. 44, 68–77 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Hashimoto, K. et al. An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc. Natl Acad. Sci. USA 98, 3998–4003 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Machado, D. S. et al. A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo. Proc. Natl Acad. Sci. USA 106, 9441–9446 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Parrilla, R., Mixson, A. J., McPherson, J. A., McClaskey, J. H. & Weintraub, B. D. Characterization of seven novel mutations of the c-erbA β gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two “hot spot” regions of the ligand binding domain. J. Clin. Invest. 88, 2123–2130 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Flynn, T. R. et al. A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition. J. Biol. Chem. 269, 32713–32716 (1994).

    CAS  PubMed  Google Scholar 

  77. Faustino, L. C. et al. Liver glutathione S-transferase α expression is decreased by T3 in hypothyroidism but not in euthyroidism in mice. Exp. Physiol. 96, 790–800 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Cordas, E. A. et al. Thyroid hormone receptors control developmental maturation of the middle ear and the size of the ossicular bones. Endocrinology 153, 1548–1560 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Richter, C. P., Munscher, A., Machado, D. S., Wondisford, F. E. & Ortiga-Carvalho, T. M. Complete activation of thyroid hormone receptor β by T3 is essential for normal cochlear function and morphology in mice. Cell Physiol. Biochem. 28, 997–1008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pessoa, C. N. et al. Thyroid hormone action is required for normal cone opsin expression during mouse retinal development. Invest. Ophthalmol. Vis. Sci. 49, 2039–2045 (2008).

    Article  PubMed  Google Scholar 

  81. Ng, L. et al. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat. Genet. 27, 94–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Roberts, M. R., Srinivas, M., Forrest, D., Morreale de Escobar, G. & Reh, T. A. Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc. Natl Acad. Sci. USA 103, 6218–6223 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Weiss, A. H., Kelly, J. P., Bisset, D. & Deeb, S. S. Reduced L- and M- and increased S-cone functions in an infant with thyroid hormone resistance due to mutations in the THRβ2 gene. Ophthalmic Genet. 33, 187–195 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Mangelsdorf, D. J. & Evans, R. M. The RXR heterodimers and orphan receptors. Cell 83, 841–850 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Hollenberg, A. N., Monden, T., Madura, J. P., Lee, K. & Wondisford, F. E. Function of nuclear co-repressor protein on thyroid hormone response elements is regulated by the receptor A/B domain. J. Biol. Chem. 271, 28516–28520 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Liu, Y., Xia, X., Fondell, J. D. & Yen, P. M. Thyroid hormone-regulated target genes have distinct patterns of coactivator recruitment and histone acetylation. Mol. Endocrinol. 20, 483–490 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Fozzatti, L. et al. Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1). Proc. Natl Acad. Sci. USA 108, 17462–17467 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Swanson, E. A. et al. Cardiac expression and function of thyroid hormone receptor β and its PV mutant. Endocrinology 144, 4820–4825 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Suarez, J., Scott, B. T., Suarez-Ramirez, J. A., Chavira, C. V. & Dillmann, W. H. Thyroid hormone inhibits ERK phosphorylation in pressure overload-induced hypertrophied mouse hearts through a receptor-mediated mechanism. Am. J. Physiol. Cell Physiol. 299, C1524–C1529 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gloss, B. et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β. Endocrinology 142, 544–550 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Gloss, B. et al. Altered cardiac phenotype in transgenic mice carrying the Δ337 threonine thyroid hormone receptor β mutant derived from the S family. Endocrinology 140, 897–902 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Ortiga-Carvalho, T. M. et al. Thyroid hormone resistance in the heart: role of the thyroid hormone receptor β isoform. Endocrinology 145, 1625–1633 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Safer, J. D. et al. Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone. Mol. Endocrinol. 11, 16–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Wagner, R. L. et al. A structural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Nagaya, T. & Jameson, J. L. Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance. J. Biol. Chem. 268, 15766–15771 (1993).

    CAS  PubMed  Google Scholar 

  96. Yen, P. M., Wilcox, E. C., Hayashi, Y., Refetoff, S. & Chin, W. W. Studies on the repression of basal transcription (silencing) by artificial and natural human thyroid hormone receptor-β mutants. Endocrinology 136, 2845–2851 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Monden, T. et al. Leucine at codon 428 in the ninth heptad of thyroid hormone receptor β1 is necessary for interactions with the transcriptional cofactors and functions regardless of dimer formations. Thyroid 13, 427–435 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Fraichard, A. et al. The T3R α gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J. 16, 4412–4420 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. O'Shea, P. J. et al. A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. Mol. Endocrinol. 17, 1410–1424 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. O'Shea, P. J. et al. Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor α1 or β. Mol. Endocrinol. 19, 3045–3059 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Quignodon, L., Vincent, S., Winter, H., Samarut, J. & Flamant, F. A point mutation in the activation function 2 domain of thyroid hormone receptor α1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism. Mol. Endocrinol. 21, 2350–2360 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Fauquier, T. et al. Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development. Development 141, 166–175 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Adams, M. et al. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor β gene. J. Clin. Invest. 94, 506–515 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tinnikov, A. et al. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor α1. EMBO J. 21, 5079–5087 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Refetoff, S., DeWind, L. T. & DeGroot L. J. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J. Clin. Endocrinol. Metab. 27, 279–294 (1967).

    Article  CAS  PubMed  Google Scholar 

  106. Liu, Y. Y., Schultz, J. J. & Brent, G. A. A thyroid hormone receptor α gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J. Biol. Chem. 278, 38913–38920 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

T.M.O.-C.'s research is supported by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ, CNE 102.873/2012) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, #303,734/2012-4) and the Bill and Melinda Gates Foundation. F.E.W.'s research is supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK49126 and the Johns Hopkins–University of Maryland Diabetes Research Center NIDDK grant P30DK79637.

Author information

Authors and Affiliations

  1. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, S/N, Cidade Universitária, Rio de Janeiro, 21941-902, Brazil

    Tânia M. Ortiga-Carvalho

  2. Departments of Paediatrics and Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 10-113, Baltimore, 21287, MD, USA

    Aniket R. Sidhaye & Fredric E. Wondisford

Authors
  1. Tânia M. Ortiga-Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aniket R. Sidhaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fredric E. Wondisford
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to all aspects of this article.

Corresponding author

Correspondence to Fredric E. Wondisford.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ortiga-Carvalho, T., Sidhaye, A. & Wondisford, F. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 10, 582–591 (2014). https://doi.org/10.1038/nrendo.2014.143

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.143

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing