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New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.

Publication ,  Journal Article
Yen, PM; Sugawara, A; Refetoff, S; Chin, WW
Published in: J Clin Invest
November 1992

Generalized resistance to thyroid hormone (GRTH) is a syndrome of hyposensitivity to triiodothyronine (T3) that displays autosomal dominant inheritance. The genetic defect commonly lies in the ligand-binding domain of one of the TR beta alleles. Since there are two major thyroid hormone receptor (TR) isoforms, TR alpha and TR beta, it is not known how the mutant receptor mediates a dominant negative effect. Previously, we showed that T3 caused dissociation of TR homodimers and TR alpha/TR beta dimers from several thyroid hormone response elements (TREs). Hence, we used the electrophoretic mobility shift assay to compare the effect of T3 on the DNA binding of mutant TR beta-1 (Mf-1) from a kindred with GRTH with normal TR beta. Mf-1 bound better as a homodimer than TR beta, but dissociated from DNA only at high T3 concentrations. Both receptors heterodimerized with nuclear auxiliary proteins. They also dimerized with TR alpha and with each other. Surprisingly, T3 disrupted the DNA binding of the Mf-1/TR isoform dimers. Thus, mechanisms for the dominant negative effect by mutant TRs likely involve either increased binding to TREs by mutant homodimers that cannot bind T3 (hence cannot dissociate from DNA) and/or the formation of inactive mutant TR/nuclear protein heterodimers.

Duke Scholars

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

November 1992

Volume

90

Issue

5

Start / End Page

1825 / 1831

Location

United States

Related Subject Headings

  • Triiodothyronine
  • Receptors, Thyroid Hormone
  • Rats
  • Mutation
  • Immunology
  • Drug Resistance
  • DNA
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

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ICMJE
MLA
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Yen, P. M., Sugawara, A., Refetoff, S., & Chin, W. W. (1992). New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone. J Clin Invest, 90(5), 1825–1831. https://doi.org/10.1172/JCI116058
Yen, P. M., A. Sugawara, S. Refetoff, and W. W. Chin. “New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.J Clin Invest 90, no. 5 (November 1992): 1825–31. https://doi.org/10.1172/JCI116058.
Yen, P. M., et al. “New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.J Clin Invest, vol. 90, no. 5, Nov. 1992, pp. 1825–31. Pubmed, doi:10.1172/JCI116058.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

November 1992

Volume

90

Issue

5

Start / End Page

1825 / 1831

Location

United States

Related Subject Headings

  • Triiodothyronine
  • Receptors, Thyroid Hormone
  • Rats
  • Mutation
  • Immunology
  • Drug Resistance
  • DNA
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences