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

研究成果: Article査読

59 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1825-1831
ページ数7
ジャーナルJournal of Clinical Investigation
90
5
DOI
出版ステータスPublished - 1992 11月
外部発表はい

ASJC Scopus subject areas

  • 医学(全般)

フィンガープリント

「New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル