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

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.