Thyroid hormone receptor mutations and disease: insights from knock-in mouse models

Thyroid hormone nuclear receptors (TRs) mediate thyroid hormone's activities in growth, differentiation, and development. Two TR genes (α and β ) encode four thyroid hormone-binding receptors that regulate target gene expression. Mutations of the TRβ gene cause the genetic syndrome of resistance to thyroid hormone. Studies indicate a close association between TRβ mutations and several human cancers, suggesting their oncogenic role. A TRβ gene knock-in mutant mouse (TRβ^PV/PV mouse) that spontaneously develops thyroid cancer allows elucidation of the oncogenic functions in vivo. TRβPV is a potent dominant negative mutant identified in a resistance to thyroid hormone patient. Molecular studies indicate that the PV mutant mediates its oncogenic activities via nucleus-initiated transcription and novel extranuclear actions. Thus, the deleterious effects of the gene mutations go beyond resistance to thyroid hormone and are more severe and extensive than previously envisioned. This newly identified oncogene exerts its tumorigenic effects via multiple signaling mechanisms.