SELECTIVE PITUITARY RESISTANCE TO THYROID-HORMONE PRODUCED BY EXPRESSION OF A MUTANT THYROID-HORMONE RECEPTOR-BETA GENE IN THE PITUITARY-GLAND OF TRANSGENIC MICE

Resistance to thyroid hormone (RTH) has been subdivided into generaliz ed resistance (GRTH) and pituitary resistance (PRTH) based on the clin ical impression of absence or presence of thyrotoxicosis, However, due to lack of objective clinical and genetic criteria, the existence of PRTH as a distinct entity became controversial. To determine what the phenotype would be if RTH was confined to the pituitary, a transgenic mouse was developed in which expression of the mutant thyroid hormone receptor (TR) beta (G345R) was targeted to the pituitary thyrotrophs b y placing it downstream of the mouse thyrotropin beta promoter. This c onstruct exhibited an antagonistic effect on the thyroid hormone-depen dent transactivation, mediated through the wild-type TR beta 1, only w hen co-transfected with the thyrotroph embryonic factor in a heterolog ous cell line. As expected the transgene was transcribed predominantly in the pituitary gland but not in liver. These mice showed a signific ant, though modest, increase in serum T-4 concentration. A decrease in the serum cholesterol was observed in keeping with the selective tiss ue hyposensitivity to thyroid hormone. (C) 1998 Academic Press.