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 mutatio ns in the thyroid hormone receptor-beta (TR beta) gene. Replication-de fective recombinant adenoviruses were constructed that express the hum an wildtype (WT) TR beta, a human mutant TR beta identified in a famil y 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. Hypothyr oid mice were infected with Luc alone and in combination with the WT T R beta or mutant TR beta. Half of the mice from each group were then t reated with T-3. Compared with mice infected with Luc alone, T-3 treat ment of mutant TR beta infected mice showed no changes in liver lucife rase, weight, or 5'-deiodinase and spot 14 messenger RNA, and the dece ase in the serum cholesterol concentration was blunted as in patients with RTH. The effects of T-3 in mice infected with WT TR beta were com parable to those in mice infected with Luc alone. However, overexpress ion of the WT TR beta tended to further increase serum cholesterol in the hypothyroid state and decrease it in response to T-3, suggesting t hat the unliganded TR has a constitutive effect in vivo and that highe r TR levels can aggravate the manifestations of hypothyroidism and enh ance the action of thyroid hormone. Transient somatic transfer of muta nt TR genes provides a model for the study of RTH. It allows evaluatio n of the effect of genetic factors interacting with mutant TRs that mo dify the phenotype of RTH, without animal back-crossing.