MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

泛发性甲状腺激素抵抗是一种甲状腺激素紊乱 以游离甲状腺激素和TSH升高为特征的作用，以及 甲状腺功能正常或不适当的临床和生化体征 甲状腺功能减退。利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，位于3号染色体上的c-erba-beta。随后我们在 10个家庭认为这种疾病是由配体结合突变引起的 β受体的结构域。在那里描述的十个家庭中的每一个 都是独特的缺陷，所有这些都导致了非保守性 氨基酸的变化改变了细胞的T3结合特性 受体，同时不会引起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的变化 在转录活动所必需的突变受体中。 我们目前正在阐明另外15个分子缺陷 在国立卫生研究院研究的家庭，正试图将独特的 该综合征具有各种临床表现的分子缺陷。我们 也试图用各种不同的方式表达高水平的受体 表达系统。这样的研究应该第一次允许 甲状腺激素(X和P)生理作用的阐明 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.