Weiss R E, Hayashi Y, Nagaya T, Petty K J, Murata Y, Tunca H, Seo H, Refetoff S
Department of Medicine, University of Chicago, Illinois 60637, USA.
J Clin Endocrinol Metab. 1996 Dec;81(12):4196-203. doi: 10.1210/jcem.81.12.8954015.
Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T3-mediated function. We describe a unique family in which the dominantly inherited RTH is not associated with abnormalities in the TR beta or TR alpha genes, as determined by gene sequencing and linkage analysis. However, affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T3 despite a normal concentration of TR, other abnormalities in the mediation of T3 action were sought. Nucleotide sequences of the TSH beta promoter, containing thyroid hormone response elements, and TR-interacting protein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblasts from affected individuals of this family were tested for their interaction with normal TR beta and thyroid hormone response elements by the electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and patients with RTH caused by TR beta mutations or deletion. Far Western analysis of NE from the affected daughter hybridized with labeled TR beta demonstrated an additional band that was not seen in NEs from a normal control or patients with TR beta gene defects. It is concluded that the etiology of RTH is not confined to abnormalities in the TR beta gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of the RTH phenotype in this family.
甲状腺激素抵抗（RTH）是一种遗传性综合征，其特征为组织对甲状腺激素的反应性降低。迄今为止，所有表现出RTH表型的个体均被发现甲状腺激素受体β（TRβ）基因存在突变，这些突变损害了T3介导的功能。我们描述了一个独特的家系，通过基因测序和连锁分析确定，该家系中显性遗传的RTH与TRβ或TRα基因的异常无关。然而，受影响的家庭成员表现出严重形式的RTH，促甲状腺细胞和外周组织的反应降低，需要8至10倍于正常替代剂量的L-T4和L-T3。未检测到其他内分泌异常。该缺陷在先证者中新生出现，并遗传给了她与不同父亲生育的两个孩子。尽管先证者的TR浓度正常，但培养的成纤维细胞对T3反应不佳，因此研究了T3作用介导过程中的其他异常情况。含有甲状腺激素反应元件的TSHβ启动子和TR相互作用蛋白1的核苷酸序列正常。通过电泳迁移率变动分析，检测了该家系受影响个体培养的皮肤成纤维细胞核提取物（NE）与正常TRβ和甲状腺激素反应元件的相互作用。与正常个体以及由TRβ突变或缺失导致的RTH患者的NE相比，先证者的NE显示出一条强烈的额外条带。对受影响女儿的NE进行Far Western分析，用标记的TRβ杂交，显示出一条在正常对照或TRβ基因缺陷患者的NE中未见的额外条带。结论是，RTH的病因不限于TRβ基因的异常。在该家系中，一种在甲状腺激素作用调节中具有特定功能的异常辅因子可能参与了RTH表型的表达。
