Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter T A, Kazlauskaite R, Pankratz D G, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham M C, Barlow C, Cheng S
Laboratory of Molecular Biology, National Cancer Institute, and Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13209-14. doi: 10.1073/pnas.230285997.
Patients with mutations in the thyroid hormone receptor beta (TRbeta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. To understand the molecular basis underlying the action of mutant TRbeta in vivo, we generated mice with a targeted mutation in the TRbeta gene (TRbetaPV; PV, mutant thyroid hormone receptor kindred PV) by using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH. Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype is distinct from that seen in mice with a null mutation in the TRbeta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TRbetaPV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild-type TR in vivo. These results show that the actions of mutant and wild-type TRbeta in vivo are distinct. This model allows further study of the molecular action of mutant TR in vivo, which could lead to better treatment for RTH patients.
甲状腺激素受体β（TRβ）基因突变的患者表现出对甲状腺激素（RTH）的抵抗，导致一系列可变的表型异常。为了了解体内突变型TRβ作用的分子基础，我们通过同源重组和Cre/loxP系统，构建了TRβ基因发生靶向突变的小鼠（TRβPV；PV，突变型甲状腺激素受体家族PV）。表达单个PV等位基因的小鼠表现出在患有RTH的杂合子人类中发现的典型甲状腺功能异常。纯合子PV小鼠表现出垂体-甲状腺轴的严重功能障碍、体重增加受损和骨骼发育异常。这种表型与TRβ基因无突变的小鼠不同。重要的是，我们在TRβPV小鼠的组织中鉴定出几个基因的异常表达模式，证明了突变型TR在体内对野生型TR基因调控功能的干扰。这些结果表明，突变型和野生型TRβ在体内的作用是不同的。该模型允许进一步研究突变型TR在体内的分子作用，这可能为RTH患者带来更好的治疗方法。
