MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

甲状腺激素抵抗(RTH)是一种遗传性疾病，与 βT_3受体基因突变，临床特征为 外周组织和垂体组织对苯丙氨酸作用的抵抗力 甲状腺激素。在发现的50多种不同的突变中 β受体的配基结合域，有几个被证明能抑制 正常的受体通过显性的负性机制发挥作用，这种机制很可能 以调节这种疾病的表型。最近的研究表明 这种显性的负面影响很可能是由竞争所调节的 突变的和正常的受体结合内的T3反应元件 各种甲状腺激素反应基因。 我们最近发现，天然的甲状腺激素反应元件 (Tre‘s)表现出显性负效应与 以前使用的人工TRE。这些差异似乎 解释RTH的不同临床特征。我们最近开发了 一种RTH转基因模型应该有助于理解 突变型受体在体内的功能及其在开发新的治疗方法中的作用 这种疾病。最后，我们开发了新的方法来筛选 使用自动化技术快速识别受体突变 DNA测序。所有这些改进都应该适用于其他 显性遗传病。

Resistance to thyroid hormone (RTH) is an inherited disease linked to mutations in the beta T3 receptor gene and characterized clinically by the resistance of peripheral and pituitary tissues to the action of thyroid hormone. Of the over 50 different mutations identified in the ligand binding domain of the beta receptor, several were shown to inhibit normal receptor function by a dominant negative mechanism which is likely to mediate the phenotype of this disease. Recent studies have indicated that this dominant negative effect is most likely mediated by competition of mutant and normal receptor for binding to T3 response elements within various thyroid hormone responsive genes. We have recently shown that natural thyroid hormone response elements (TRE's) show variation in the dominant negative effect compared to previously employed artificial TRE's. These differences appear to explain the diverse clinical features of RTH. We have recently developed a transgenic model of RTH which should be useful in understanding the function of mutant receptors in vivo and in developing new therapies for the disease. Finally, we have developed novel methods to screen for mutations in the receptor to identify mutations rapidly using automated DNA sequencing. All of these advances should be applicable to other dominant genetic diseases.