Expression of the Mutant Thyroid Hormone Receptor PV in the Pituitary of Transgenic Mice Leads to Weight Reduction

Abstract

Resistance to thyroid hormone (RTH) is a genetic disease caused by mutations of the thyroid hormone receptor β gene (TRβ). One of the symptoms in some affected individuals is growth retardation. To understand the molecular basis of growth retardation in these patients with RTH, a transgenic mouse was prepared in which the expression of the TRβ1 mutant PV was targeted to the pituitary using the promoter of the glycoprotein hormone α-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 TRβ gene and leads to a frame-shift of the carboxyl-terminal 14 amino acids of TRβ1, resulting in total loss of triiodothyronine (T₃) binding and transcriptional activation. PV was selectively expressed in the pituitary of the transgenic mouse and not in other tissues examined. The transgenic mice showed a significant impairment in weight gain. However, no changes in the serum level of thyroid-stimulating hormone were seen, and no elevation of thyroid hormones was detected in the transgenic mice. The circulating levels of growth hormone and insulin-like growth factor I were not affected in the transgenic mice, suggesting that the growth impairment in RTH is complex and is mediated by pathways that are yet to be elucidated.