MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

全身性甲状腺激素抵抗是一种甲状腺激素紊乱 作用特点是游离甲状腺激素和TSH升高，以及 甲状腺功能正常的不适当的临床和生化体征，或 甲状腺功能减退使用限制性片段长度多态性，我们 最初将这种疾病与两种已知的甲状腺激素之一联系起来， 受体基因，3号染色体上的c-erbA-β。随后，我们在 10个家庭认为，这种疾病是由突变的配体结合 β受体的结构域。在每十个家庭的特点有 都是独特的缺陷，所有这些都导致了非保守性 改变了T3结合特性的氨基酸的变化 受体，而不引起DNA结合特性的明显变化。这些 数据表明，T3结合的减少阻止了构象变化 转录活性所必需的突变受体。 我们目前正在阐明另外15个中的分子缺陷。 美国国立卫生研究院研究的家庭，并试图将独特的 分子缺陷与此综合征的各种临床表现。我们 也试图用各种方法表达高水平的受体， 表达系统。这些研究应该首次允许 阐明甲状腺激素的生理作用 调节人体甲状腺激素作用的受体。

Generalized thyroid hormone resistance is a disorder of thyroid hormone action characterized by elevated free thyroid hormones and TSH, as well as inappropriate clinical and biochemical signs of euthyroidism or hypothyroidism. Using restriction fragment length polymorphism, we initially linked this disorder to one of the two known thyroid hormone receptor genes, c-erbA-beta on chromosome 3. Subsequently we have shown in ten families that this disease is caused by mutations in the ligand binding domain of the beta receptor. In each of ten families characterized there have been unique defects all of which have resulted in nonconservative changes in amino acids that have altered the T3 binding properties of the receptor, while causing no apparent change in DNA binding properties. These data suggest that decreased binding of T3 prevents a conformational change in the mutant receptor necessary for transcriptional activity. We are currently elucidating the molecular defects in an additional 15 families studied at NIH and are attempting to correlate the unique molecular defects with various clinical manifestations of this syndrome. We are also attempting to express high levels of the receptor using various expression systems. Such studies should allow for the first time an elucidation of the physiologic role of the (X and P thyroid hormone receptors for mediating thyroid hormone action in man.