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.