Hayashi Y, Mangoura D, Refetoff S
Department of Medicine, University of Chicago, Illinois 60637, USA.
Mol Endocrinol. 1996 Jan;10(1):100-6. doi: 10.1210/mend.10.1.8838149.
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.
甲状腺激素抵抗（RTH）是一种显性遗传综合征，其特征是由于甲状腺激素受体β（TRβ）基因突变导致对甲状腺激素不敏感。构建了复制缺陷型重组腺病毒，其在甲状腺激素（Luc）的控制下表达人野生型（WT）TRβ、在一个RTH家族中鉴定出的人突变型TRβ和荧光素酶。通过免疫细胞化学证实了这些重组基因有效导入成年小鼠肝脏并在其中表达。用Luc单独或与WT TRβ或突变型TRβ联合感染甲状腺功能减退的小鼠。然后每组一半的小鼠用T3治疗。与单独感染Luc的小鼠相比，用T3治疗感染突变型TRβ的小鼠，其肝脏荧光素酶、体重、5'-脱碘酶和spot 14信使核糖核酸没有变化，血清胆固醇浓度的降低也如RTH患者一样受到抑制。T3对感染WT TRβ的小鼠的影响与对感染Luc的小鼠的影响相当。然而，WT TRβ的过表达倾向于在甲状腺功能减退状态下进一步升高血清胆固醇，并在对T3反应时降低血清胆固醇，这表明未结合配体的TR在体内具有组成性作用，并且较高的TR水平可加重甲状腺功能减退的表现并增强甲状腺激素的作用。突变型TR基因的瞬时体细胞转移为RTH的研究提供了一个模型。它允许在不进行动物回交的情况下评估与修饰RTH表型的突变型TR相互作用的遗传因素的作用。
