A mouse model of resistance to thyroid hormone produced by somatic gene transfer of a mutant thyroid hormone receptor.
Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by hyposensitivity to thyroid hormone caused by mutations in the thyroid hormone receptor-beta (TR beta) gene. Replication-defective recombinant adenoviruses were constructed that express the human wild-type (WT) TR beta, a human mutant TR beta identified in a family with RTH, and luciferase under the control of thyroid hormone (Luc). The efficient introduction and expression of these recombinant genes into adult mouse liver were confirmed by immunocytochemistry. Hypothyroid mice were infected with Luc alone and in combination with the WT TR beta or mutant TR beta. Half of the mice from each group were then treated with T3. Compared with mice infected with Luc alone, T3 treatment of mutant TR beta infected mice showed no changes in liver luciferase, weight, or 5'-deiodinase and spot 14 messenger RNA, and the decrease in the serum cholesterol concentration was blunted as in patients with RTH. The effects of T3 in mice infected with WT TR beta were comparable to those in mice infected with Luc alone. However, overexpression of the WT TR beta tended to further increase serum cholesterol in the hypothyroid state and decrease it in response to T3, suggesting that the unliganded TR has a constitutive effect in vivo and that higher TR levels can aggravate the manifestations of hypothyroidism and enhance the action of thyroid hormone. Transient somatic transfer of mutant TR genes provides a model for the study of RTH. It allows evaluation of the effect of genetic factors interacting with mutant TRs that modify the phenotype of RTH, without animal back-crossing.
Hayashi
Y
Y
Department of Medicine, University of Chicago, Illinois 60637, USA.
Mangoura
D
D
Refetoff
S
S
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D004351:Drug Resistance / Q000235:genetics*; D018014:Gene Transfer Techniques; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D011993:Recombinant Fusion Proteins; D013963:Thyroid Hormones / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology
D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D013963:Thyroid Hormones; D014284:Triiodothyronine; D002784:Cholesterol