TRANSGENIC MICE BEARING A HUMAN MUTANT THYROID-HORMONE BETA-1 RECEPTOR MANIFEST THYROID-FUNCTION ANOMALIES, WEIGHT-REDUCTION, AND HYPERACTIVITY

Background: Resistance to thyroid hormone (RTH) is a syndrome characte rized by refractoriness of the pituitary and/or peripheral tissues to the action of thyroid hormone. Mutations in the thyroid hormone recept or beta (TR beta) gene result in TR beta 1 mutants that mediate the cl inical phenotype by interfering with transcription of thyroid hormone- regulated genes via a dominant negative effect. Ln this study, we deve loped transgenic mice harboring PV, a potent dominant negative human m utant TR beta 1 devoid of thyroid hormone binding and transcriptional activation, as an animal model to understand the molecular basis of th is human disease. Materials and Methods: Standard molecular biology ap proaches were used to obtain a cDNA fragment containing mutant PV whic h was injected into the pronucleus of fertilized egg. Founders were id entified by Southern analysis and the expression of PV in tissues was determined by RNA and immunohistochemistry. Thyroid function was deter mined by radioimmunoassays of the hormones and the behavior of mice wa s observed using standard methods. Results: The expression of mutant P V was directed by the beta-actin promoter. Mutant PV mRNA was detected in all tissues of transgenic mice, but the levels varied with tissues and with different lines of founders. Thyroid function tests in trans genic mice with high expression of mutant PV showed a significantly (s imilar to 1.5-fold) higher mean serum total of L-thyroxine levels (p < 0.01) than those of nontransgenic mice. Moreover, thyroid-stimulating hormone levels were not significantly different from those of nontran sgenic mice. Zn addition, these mice displayed decreased weights and a behavioral phenotype characterized by hyperactivity. Conclusions: The se mice have phenotypic features consistent with the commonly observed clinical features of RTH and could be used as a model system to bette r understand the action of mutant TR beta 1 in a physiological context , which could lead to better treatment for this disease.