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

Paul M. Yen, Akira Sugawara, Samuel Refetoff, William W. Chin

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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 TRβ alleles. Since there are two major thyroid hormone receptor (TR) isoforms, TRα and TRβ, it is not known how the mutant receptor mediates a dominant negative effect. Previously, we showed that T3 caused dissociation of TR homodimers and TRα/TRβ 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 TRβ-1 (Mf-1) from a kindred with GRTH with normal TRβ. Mf-1 bound better as a homodimer than TRβ, but dissociated from DNA only at high T3 concentrations. Both receptors heterodimerized with nuclear auxiliary proteins. They also dimerized with TRα 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.

Original languageEnglish
Pages (from-to)1825-1831
Number of pages7
JournalJournal of Clinical Investigation
Volume90
Issue number5
DOIs
Publication statusPublished - 1992 Nov

Keywords

  • DNA binding
  • Heterodimer
  • Homodimer
  • Thyroid hormone receptor
  • Thyroid hormone resistance

ASJC Scopus subject areas

  • Medicine(all)

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