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Multi-Factorial Regulation of in Vivo Action of TRβ Mutants. Lessons Learned from RTH Mice with a Targeted Mutation in the TRβ Gene

  • Sheue-yann Cheng
Chapter
Part of the Endocrine Updates book series (ENDO, volume 22)

Abstract

The discovery that there is tight linkage between the affected family members of resistance to thyroid hormone (RTH) and the thyroid hormone receptor β (TRβ) gene locus ushered in an exciting opportunity to study the molecular basis of RTH (1). Indeed, shortly thereafter, a Pro453His mutation was identified in the TRβ gene of one kindred (2) and a Gly345rg mutation in another (3), establishing that mutations of the TRβ gene cause RTH. To date, about 100 different mutations in the TRβ gene have been reported in more than 300 families (4).

Keywords

Thyroid Hormone Thyroid Hormone Receptor Myosin Heavy Chain Gene Circulate Thyroid Hormone Dominant Negative Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Usala, S.J., Bale, A.E., Gesundheit, N., Weinberger, C., Lash, R.W., Wondisford, F.E., McBride, O.W., and Weintraub, B.D. 1988. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c–erbA beta gene. Mol Endocrinol. 2:1217–1220.PubMedCrossRefGoogle Scholar
  2. 2.
    Usala, S.J., Tennyson, G.E., Bale, A.E., Lash, R.W., Gesundheit, N., Wondisford, F.E., Accili, D., Hauser, P., and Weintraub, B.D. 1990. A base mutation of the C–erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest. 85:93–100.CrossRefGoogle Scholar
  3. 3.
    Sakurai, A., Takeda, K., Ain, K., Ceccarelli, P., Nakai, A., Seino, S., Bell, G.I., Refetoff, S., and DeGroot, L.J. 1989. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc. Natl. Acad. Sci. USA 86:8977–8981.PubMedCrossRefGoogle Scholar
  4. 4.
    Weiss, R., and Refetoff, S. 2000. Rev. Endocr. Metab. Disord. 1:97–108.PubMedCrossRefGoogle Scholar
  5. 5.
    Wong, R., Vasilyev, V.V., Ting, Y.T., Kutler, D.I., Willingham, M.C., Weintraub, B.D., and Cheng, S. 1997. Transgenic mice bearing a human mutant thyroid hormone beta 1 receptor manifest thyroid function anomalies, weigh reduction, and hyperactivity. Mol Med. 3:303–314.PubMedGoogle Scholar
  6. 6.
    Zhu, X.G., Kaneshige, M., Parlow, A.F., Chen, E., Hunziker, R.D., McDonald, M.P., and Cheng, S.Y. 1999. Expression of the mutant thyroid hormone receptor PV in the pituitary of transgenic mice leads to weight reduction. Thyroid 9:1137–1145. PubMedCrossRefGoogle Scholar
  7. 7.
    Hayashi, Y., Xie, J., Weiss, R.E., Pohlenz, J., and Refetoff, S. 1998. Selective pituitary resistance to thyroid hormone produced by expression of a mutant thyroid hormone receptor beta gene in the pituitary gland of transgenic mice. Biochem. Biophys. Res. Commun. 245:204–210.PubMedCrossRefGoogle Scholar
  8. 8.
    Abel, E.D., Kaulbach, H.C., Campos-Barros, A., Ahima, R.S., Boers, M.E., Hashimoto, K., Forrest, D., and Wondisford, F.E. 1999. Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin. J.Clin. Invest. 103:271–279.CrossRefGoogle Scholar
  9. 9.
    Hayashi Y, Mangoura D, Refetoff S.1996 A mouse model of resistance to thyroid hormone produced by somatic gene transfer of a mutant thyroid hormone receptor. Mol Endocrinol. 10:100–106.PubMedCrossRefGoogle Scholar
  10. 10.
    Kaneshige, M., Kaneshige, K., Zhu, X., Dace, A., Garrett, L., Carter, T.A., Kazlauskaite, R., Pankratz, D.G., Wynshaw-Boris, A., Refetoff, Weintraub, B., et al. 2000. Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci USA 97:13209–13214PubMedCrossRefGoogle Scholar
  11. 11.
    Hashimoto, K., Curty, F.H., Borges, P.P., Lee, C.E., Abel, E.D., Elmquist, J.K., Cohen, R.N., and Wondisford, F.E. 2001. An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc. Natl. Acad. Sci. USA 98:3998–4003.PubMedCrossRefGoogle Scholar
  12. 12.
    Parrilla, R., Mixson, A.J., McPherson, J.A., McClaskey, J.H., and Weintraub, B.D. 1991. Characterization of seven novel mutations of the c-erbA beta 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.PubMedCrossRefGoogle Scholar
  13. 13.
    Bhat, M.K., McPhie, P., Ting, Y.T., Zhu, X.G., and Cheng, S.Y. 1995. Structure of the carboxy-terminal region of thyroid hormone nuclear receptors and its possible role in hormone-dependent intermolecular interactions. Biochemistry 34:10591–10599.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang, X.Y., Kaneshige, M., Kamiya, Y., Kaneshige, K., McPhie, P., and Cheng, S.Y. 2002. Differential expression of thyroid hormone receptor isoforms dictates the dominant negative activity of mutant Beta receptor. Mol. Endocrinol. 16:2077–2092.PubMedCrossRefGoogle Scholar
  15. 15.
    Ono, S., Schwartz, I.D., Mueller, O.T., Root, A.W., Usala, S.J., and Bercu, B.B. 1991. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J. Clin. Endocrinol. Metab. 73:990–994.PubMedCrossRefGoogle Scholar
  16. 16.
    Usala, S.J., Menke, J.B., Watson, T.L., Wondisford, F.E., Weintraub, B.D., Berard, J., Bradley, W.E., Ono, S., Mueller, O.T., and Bercu, B.B. 1991. A homozygous deletion in the cerbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol. Endocrinol. 5:327–335.PubMedCrossRefGoogle Scholar
  17. 17.
    Brucker-Davis, F., Skarulis, M.C., Grace, M.B., Benichou, J., Hauser, P., Wiggs, E., and Weintraub, B.D. 1995. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann. Intern. Med. 123:572–583.PubMedGoogle Scholar
  18. 18.
    Griffith, A.J., Szymko, Y.M., Kaneshige, M., Quinonez, R.E., Kaneshige, K., Heintz, K.A., Mastroianni, M.A., Kelley, M.W., and Cheng, S.Y. 2002. Knockin mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis. J. Assoc. Res. Otolaryngol. 3:279–288.PubMedCrossRefGoogle Scholar
  19. 19.
    Hauser, P., Zametkin, A.J., Martinez, P., Vitiello, B., Matochik, J.A., Mixson, A.J., and Weintraub, B.D. 1993. Attention deficithyperactivity disorder in people with generalized resistance to thyroid hormone. N. Engl. J. Med. 328:997–1001.PubMedCrossRefGoogle Scholar
  20. 20.
    Meier, C.A., Dickstein, B.M., Ashizawa, K., McClaskey, J.H., Muchmore, P., Ransom, S.C., Merke, J.B., Hao, E.U., Usala, S.J., Bercu, B.B., et al. 1992. Variable transcriptional activity and ligand binding of mutant 2751; 1 3,3,5-triiodo-Lthyronine receptors from four families with generalized resistance to thyroid hormone. Mol. Endocrinol. 6:248–258.PubMedCrossRefGoogle Scholar
  21. 21.
    Meier, C.A., Parkison, C., Chen, A., Ashizawa, K., Muchmore, P., Meier-Heusler, S.C., Cheng, S.-y., and Weintraub, B.D. 1993. Interaction of human 01 thyroid hormone receptor and its mutants with DNA and RXR 2751; . T3 response element-dependent dominant negative potency. J. Clin. Invest. 92:1986–1993.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhu, X.G., Yu, C.L., McPhie, P., Wong, R., and Cheng, S.Y. 1996. Understanding the molecular mechanism of dominant negative action of mutant thyroid hormone beta 1–receptors: the important role of the wildtype/mutant receptor heterodimer. Endocrinology 137:712–721.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu, X.G., McPhie, P., and Cheng, S.Y. 1997. Differential sensitivity of thyroid hormone receptor isoform homodimers and mutant heterodimers to hormone-induced dissociation from deoxyribonucleic acid: its role in dominant negative action. Endocrinology 138:1456–1463.PubMedCrossRefGoogle Scholar
  24. 24.
    Beck-Peccoz, P., and Chatterjee, V.K. 1994. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 4:225–232.PubMedCrossRefGoogle Scholar
  25. 25.
    Refetoff, S., Weiss, R.E., and Usala, S.J. 1993. The syndromes of resistance to thyroid hormone. Endocr. Rev. 14:348–399.PubMedGoogle Scholar
  26. 26.
    Wagner, R.L., Apriletti, J.W., McGrath, M.E., West, B.L., Baxter, J.D., and Fletterick, R.J. 1995. A structural role for hormone in the thyroid hormone receptor Nature 378:690–697.PubMedCrossRefGoogle Scholar
  27. 27.
    Cheng, S.Y. 2000. Multiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors. Rev. Endocr. Metab. Disorder 1:9–18.CrossRefGoogle Scholar
  28. 28.
    Gloss, B., Sayen, M.R., Trost, S.U., Bluhm, W.F., Meyer, M., Swanson, E.A., Usala, S.J., and Dillmann, W.H. 1999. Altered cardiac phenotype in transgenic mice carrying the 337 threonine thyroid hormone receptor β mutant derived from the S family. Endocrinology 140:897–902.PubMedCrossRefGoogle Scholar
  29. 29.
    McKenna, N.J., Lanz, R.B., and O’Malley, B.W. 1999. Nuclear receptor coregulators: cellular and molecular biology. Endocrinol. Rev. 20:321–344.CrossRefGoogle Scholar
  30. 30.
    McKenna, N.J., and O’Malley, B.W. 2002. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108: 465–474.PubMedCrossRefGoogle Scholar
  31. 31.
    Hermanson, O., Glass, C.K., and Rosenfeld, M.G. 2002. Nuclear receptor coregulators: multiple modes of modification. Trends Endocrinol. Metab. 13:55–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Horlein, A.J., Naar, A.M., Heinzel, T., Torchia, J., Gloss, B., Kurokawa, R., Ryan, A., Kamei, Y., Soderstrom, M., Glass, C.K., et al. 1995. Ligandindependent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor. Nature 377:397–404.PubMedCrossRefGoogle Scholar
  33. 33.
    Chen, J.D., and Evans, R.M. 1995. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457.PubMedCrossRefGoogle Scholar
  34. 34.
    Heinzel, T., Lavinsky, R.M., Mullen, T.M., Soderstrom, M., Laherty, C.D., Torchia, J., Yang, W.M., Brard, G., Ngo, S.D., Davie, J.R., et al. 1997. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43–48.PubMedCrossRefGoogle Scholar
  35. 35.
    Weiss, R.E., Xu, J., Ning, G., Pohlenz, J., O’Malley, B.W., and Refetoff, S. 1999. Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J. 18:1900–1904.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Sheue-yann Cheng
    • 1
  1. 1.Gene Regulation Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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