Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1991 Jun;87(6):1977–1984. doi: 10.1172/JCI115225

Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors.

V K Chatterjee 1, T Nagaya 1, L D Madison 1, S Datta 1, A Rentoumis 1, J L Jameson 1
PMCID: PMC296951  PMID: 2040690

Abstract

Thyroid hormone (T3) resistance is inherited in most cases in an autosomal dominant manner. The disorder is characterized by elevated free thyroid hormone levels and partial resistance to thyroid hormone at the cellular level. Distinct single amino acid substitutions in the ligand binding domain of the beta form of the thyroid hormone receptor have been described in two kindreds with this disorder. We used transient expression assays to characterize the functional properties of these receptor mutants, one containing a Gly to Arg change at amino acid 340 (G340R) and the other a Pro to His change at amino acid 448 (P448H). A nine amino acid carboxy terminal deletion (delta 448-456), analogous to an alteration that occurs in v-erbA, was also studied for comparison with the mutations that occur in the T3 resistance syndrome. None of the receptor mutants were able to mediate thyroid hormone dependent activation (TreTKCAT) or repression (TSH alpha CAT) of reporter genes when compared with the wild type receptor. In addition, the mutants inhibited the activity of normal alpha and beta receptor isoforms when examined in coexpression assays. This activity, referred to as dominant negative inhibition, was manifest with respect to both the positively and negatively regulated reporter genes. Although mutant receptor binding to DNA was unaffected, ligand binding studies showed that the G340R and delta 448-456 mutants failed to bind T3, whereas the P448H mutant bound hormone with reduced affinity (approximately 10% of normal) compared to the wild type receptor. Consistent with this finding, the P448H mutant receptor was partially active at higher T3 concentrations. Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3. These findings indicate that mutant beta receptors in patients with thyroid hormone resistance have reduced affinity for T3 and are functionally deficient, but impair the activity of normal receptors, thereby providing a mechanism for the dominant mode of inheritance in this disorder.

Full text

PDF
1977

Images in this article

1978Image
on p.1978
1979Image
on p.1979
1979Image
on p.1979
1979Image
on p.1979
1979Image
on p.1979
1980Image
on p.1980
1981Image
on p.1981
1981Image
on p.1981
1981Image
on p.1981
1981Image
on p.1981
1982Image
on p.1982

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abel T., Maniatis T. Gene regulation. Action of leucine zippers. Nature. 1989 Sep 7;341(6237):24–25. doi: 10.1038/341024a0. [DOI] [PubMed] [Google Scholar]
  2. Benezra R., Davis R. L., Lockshon D., Turner D. L., Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990 Apr 6;61(1):49–59. doi: 10.1016/0092-8674(90)90214-y. [DOI] [PubMed] [Google Scholar]
  3. Brent G. A., Harney J. W., Chen Y., Warne R. L., Moore D. D., Larsen P. R. Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element. Mol Endocrinol. 1989 Dec;3(12):1996–2004. doi: 10.1210/mend-3-12-1996. [DOI] [PubMed] [Google Scholar]
  4. Burnside J., Darling D. S., Chin W. W. A nuclear factor that enhances binding of thyroid hormone receptors to thyroid hormone response elements. J Biol Chem. 1990 Feb 15;265(5):2500–2504. [PubMed] [Google Scholar]
  5. Chatterjee V. K., Lee J. K., Rentoumis A., Jameson J. L. Negative regulation of the thyroid-stimulating hormone alpha gene by thyroid hormone: receptor interaction adjacent to the TATA box. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9114–9118. doi: 10.1073/pnas.86.23.9114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Damm K., Thompson C. C., Evans R. M. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature. 1989 Jun 22;339(6226):593–597. doi: 10.1038/339593a0. [DOI] [PubMed] [Google Scholar]
  7. Dwarki V. J., Montminy M., Verma I. M. Both the basic region and the 'leucine zipper' domain of the cyclic AMP response element binding (CREB) protein are essential for transcriptional activation. EMBO J. 1990 Jan;9(1):225–232. doi: 10.1002/j.1460-2075.1990.tb08099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Forman B. M., Samuels H. H. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol. 1990 Sep;4(9):1293–1301. doi: 10.1210/mend-4-9-1293. [DOI] [PubMed] [Google Scholar]
  9. Forman B. M., Yang C. R., Au M., Casanova J., Ghysdael J., Samuels H. H. A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors. Mol Endocrinol. 1989 Oct;3(10):1610–1626. doi: 10.1210/mend-3-10-1610. [DOI] [PubMed] [Google Scholar]
  10. Glass C. K., Lipkin S. M., Devary O. V., Rosenfeld M. G. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer. Cell. 1989 Nov 17;59(4):697–708. doi: 10.1016/0092-8674(89)90016-0. [DOI] [PubMed] [Google Scholar]
  11. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  13. Hodin R. A., Lazar M. A., Wintman B. I., Darling D. S., Koenig R. J., Larsen P. R., Moore D. D., Chin W. W. Identification of a thyroid hormone receptor that is pituitary-specific. Science. 1989 Apr 7;244(4900):76–79. doi: 10.1126/science.2539642. [DOI] [PubMed] [Google Scholar]
  14. Hughes M. R., Malloy P. J., Kieback D. G., Kesterson R. A., Pike J. W., Feldman D., O'Malley B. W. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science. 1988 Dec 23;242(4886):1702–1705. doi: 10.1126/science.2849209. [DOI] [PubMed] [Google Scholar]
  15. Ichikawa K., Hughes I. A., Horwitz A. L., DeGroot L. J. Characterization of nuclear thyroid hormone receptors of cultured skin fibroblasts from patients with resistance to thyroid hormone. Metabolism. 1987 Apr;36(4):392–399. doi: 10.1016/0026-0495(87)90214-9. [DOI] [PubMed] [Google Scholar]
  16. Inoue A., Yamakawa J., Yukioka M., Morisawa S. Filter-binding assay procedure for thyroid hormone receptors. Anal Biochem. 1983 Oct 1;134(1):176–183. doi: 10.1016/0003-2697(83)90280-4. [DOI] [PubMed] [Google Scholar]
  17. Izumo S., Mahdavi V. Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature. 1988 Aug 11;334(6182):539–542. doi: 10.1038/334539a0. [DOI] [PubMed] [Google Scholar]
  18. Koenig R. J., Lazar M. A., Hodin R. A., Brent G. A., Larsen P. R., Chin W. W., Moore D. D. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature. 1989 Feb 16;337(6208):659–661. doi: 10.1038/337659a0. [DOI] [PubMed] [Google Scholar]
  19. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lazar M. A., Berrodin T. J. Thyroid hormone receptors form distinct nuclear protein-dependent and independent complexes with a thyroid hormone response element. Mol Endocrinol. 1990 Nov;4(11):1627–1635. doi: 10.1210/mend-4-11-1627. [DOI] [PubMed] [Google Scholar]
  21. Lazar M. A., Chin W. W. Regulation of two c-erbA messenger ribonucleic acids in rat GH3 cells by thyroid hormone. Mol Endocrinol. 1988 Jun;2(6):479–484. doi: 10.1210/mend-2-6-479. [DOI] [PubMed] [Google Scholar]
  22. Magner J. A., Petrick P., Menezes-Ferreira M. M., Stelling M., Weintraub B. D. Familial generalized resistance to thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125I] triiodothyronine to fibroblast nuclei. J Endocrinol Invest. 1986 Dec;9(6):459–470. doi: 10.1007/BF03346968. [DOI] [PubMed] [Google Scholar]
  23. Martin K. J., Lillie J. W., Green M. R. Evidence for interaction of different eukaryotic transcriptional activators with distinct cellular targets. Nature. 1990 Jul 12;346(6280):147–152. doi: 10.1038/346147a0. [DOI] [PubMed] [Google Scholar]
  24. Menezes-Ferreira M. M., Eil C., Wortsman J., Weintraub B. D. Decreased nuclear uptake of [125I]triiodo-L-thyronine in fibroblasts from patients with peripheral thyroid hormone resistance. J Clin Endocrinol Metab. 1984 Dec;59(6):1081–1087. doi: 10.1210/jcem-59-6-1081. [DOI] [PubMed] [Google Scholar]
  25. Meyer M. E., Gronemeyer H., Turcotte B., Bocquel M. T., Tasset D., Chambon P. Steroid hormone receptors compete for factors that mediate their enhancer function. Cell. 1989 May 5;57(3):433–442. doi: 10.1016/0092-8674(89)90918-5. [DOI] [PubMed] [Google Scholar]
  26. Murray M. B., Towle H. C. Identification of nuclear factors that enhance binding of the thyroid hormone receptor to a thyroid hormone response element. Mol Endocrinol. 1989 Sep;3(9):1434–1442. doi: 10.1210/mend-3-9-1434. [DOI] [PubMed] [Google Scholar]
  27. Nakai A., Sakurai A., Bell G. I., DeGroot L. J. Characterization of a third human thyroid hormone receptor coexpressed with other thyroid hormone receptors in several tissues. Mol Endocrinol. 1988 Nov;2(11):1087–1092. doi: 10.1210/mend-2-11-1087. [DOI] [PubMed] [Google Scholar]
  28. Nakai A., Seino S., Sakurai A., Szilak I., Bell G. I., DeGroot L. J. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2781–2785. doi: 10.1073/pnas.85.8.2781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. doi: 10.1038/335683a0. [DOI] [PubMed] [Google Scholar]
  30. 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. 1967 Feb;27(2):279–294. doi: 10.1210/jcem-27-2-279. [DOI] [PubMed] [Google Scholar]
  31. Refetoff S. Syndromes of thyroid hormone resistance. Am J Physiol. 1982 Aug;243(2):E88–E98. doi: 10.1152/ajpendo.1982.243.2.E88. [DOI] [PubMed] [Google Scholar]
  32. Rentoumis A., Chatterjee V. K., Madison L. D., Datta S., Gallagher G. D., Degroot L. J., Jameson J. L. Negative and positive transcriptional regulation by thyroid hormone receptor isoforms. Mol Endocrinol. 1990 Oct;4(10):1522–1531. doi: 10.1210/mend-4-10-1522. [DOI] [PubMed] [Google Scholar]
  33. Sakurai A., Nakai A., DeGroot L. J. Expression of three forms of thyroid hormone receptor in human tissues. Mol Endocrinol. 1989 Feb;3(2):392–399. doi: 10.1210/mend-3-2-392. [DOI] [PubMed] [Google Scholar]
  34. Sakurai A., Takeda K., Ain K., Ceccarelli P., Nakai A., Seino S., Bell G. I., Refetoff S., DeGroot L. J. 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 U S A. 1989 Nov;86(22):8977–8981. doi: 10.1073/pnas.86.22.8977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schueler P. A., Schwartz H. L., Strait K. A., Mariash C. N., Oppenheimer J. H. Binding of 3,5,3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol. 1990 Feb;4(2):227–234. doi: 10.1210/mend-4-2-227. [DOI] [PubMed] [Google Scholar]
  36. Usala S. J., Bale A. E., Gesundheit N., Weinberger C., Lash R. W., Wondisford F. E., McBride O. W., Weintraub B. D. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene. Mol Endocrinol. 1988 Dec;2(12):1217–1220. doi: 10.1210/mend-2-12-1217. [DOI] [PubMed] [Google Scholar]
  37. Usala S. J., Tennyson G. E., Bale A. E., Lash R. W., Gesundheit N., Wondisford F. E., Accili D., Hauser P., Weintraub B. D. 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. 1990 Jan;85(1):93–100. doi: 10.1172/JCI114438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Usala S. J., Wondisford F. E., Watson T. L., Menke J. B., Weintraub B. D. Thyroid hormone and DNA binding properties of a mutant c-erbA beta receptor associated with generalized thyroid hormone resistance. Biochem Biophys Res Commun. 1990 Sep 14;171(2):575–580. doi: 10.1016/0006-291x(90)91185-u. [DOI] [PubMed] [Google Scholar]
  39. Weinberger C., Thompson C. C., Ong E. S., Lebo R., Gruol D. J., Evans R. M. The c-erb-A gene encodes a thyroid hormone receptor. Nature. 1986 Dec 18;324(6098):641–646. doi: 10.1038/324641a0. [DOI] [PubMed] [Google Scholar]
  40. Yaoita Y., Shi Y. B., Brown D. D. Xenopus laevis alpha and beta thyroid hormone receptors. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7090–7094. doi: 10.1073/pnas.87.18.7090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zenke M., Muñoz A., Sap J., Vennström B., Beug H. v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA. Cell. 1990 Jun 15;61(6):1035–1049. doi: 10.1016/0092-8674(90)90068-p. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES