Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor β in Mice by the Ablation of One Wild-Type β Allele

Mutations in the thyroid hormone receptor (TR) β gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRβ mutation (TRβPV) with mice carrying a TRβ null mutation (TRβ−/−) to determine the consequences of the TRβPV mutation in the absence of wild-type TRβ. TRβPV/− mice are distinct from TRβ+/− mice that did not show abnormalities in thyroid function tests. TRβPV/− mice are also distinct from TRβPV/+ and TRβ−/− mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRβPV/PV mice. Similar to TRβPV/PV mice, TRβPV/− mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRβPV/− and TRβPV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRα1 for binding to thyroid hormone response elements in TRβPV/− mice as effectively as in TRβPV/PV mice. Thus, the actions of mutant TRβ are markedly potentiated by the ablation of the second TRβ allele, suggesting that interference with wild-type TRα1-mediated gene regulation by mutant TRβ leads to severe RTH.