Expression of the mutant thyroid hormone receptor PV in the pituitary of transgenic mice leads to weight reduction

Resistance to thyroid hormone (RTH) is a genetic disease caused by mutation s of the thyroid hormone receptor beta gene (TR beta). One of the symptoms in some affected individuals is growth retardation. To understand the molec ular basis of growth retardation in these patients with RTH, a transgenic m ouse was prepared in which the expression of the TR beta 1 mutant PV was ta rgeted to the pituitary using the promoter of the glycoprotein hormone alph a-subunit. The PV mutant was originally identified in a patient with severe growth impairment. The PV mutation is a C-insertion at codon 448 of the TR beta gene and leads to a frame-shift of the carboxyl-terminal 14 amino aci ds of TR beta 1, resulting in total loss of triiodothyronine (T-3) binding and transcriptional activation. PV was selectively expressed in the pituita ry of the transgenic mouse and not in other tissues examined. The transgeni c mice showed a significant impairment in weight gain. However, no changes in the serum level of thyroid-stimulating hormone were seen, and no elevati on of thyroid hormones was detected in the transgenic mice. The circulating levels of growth hormone and insulin-like growth factor I were not affecte d in the transgenic mice, suggesting that the growth impairment in RTH is c omplex and is mediated by pathways that are yet to be elucidated.