Institute of Experimental Pediatric Endocrinology, Charite Universitatsmedizin Berlin, Augustenburger Platz, Berlin, Germany.
Front Biosci (Landmark Ed). 2010 Jun 1;15(3):913-33. doi: 10.2741/3654.
Naturally occurring activating and inactivating mutations of the thyrotropin receptor (TSHR) were found as a molecular cause of diseases in patients suffering from non-autoimmune hyperthyroidism and syndromes of thyrotropin resistance, respectively. These mutations are mostly functionally characterized in vitro and therefore, they represent an excellent tool to study structure-function relationships of this G-protein-coupled receptor. In this review, we summarize published germline mutations of the TSHR with focus on 1) the phenotype of (pediatric) patients, 2) potential genotype/phenotype correlations, 3) structural implications for receptor activation and inactivation, 4) the impact on thyroid growth, and 5) finally on aspects of TSHR dimerization. In conclusion, this comprehensive analysis of medical and biological data opens an avenue to understand genetic defects and malfunctions of the TSHR in molecular detail and in their entirety. This knowledge is important to refine our insights in non-autoimmune diseases caused by defects of the TSHR gene and it might help to develop pharmacological means for compensation of uncontrolled thyroid growth.
天然存在的促甲状腺激素受体 (TSHR) 的激活和失活突变分别被发现是导致非自身免疫性甲状腺功能亢进症和促甲状腺激素抵抗综合征患者疾病的分子原因。这些突变主要在体外进行功能表征，因此，它们是研究该 G 蛋白偶联受体结构-功能关系的极好工具。在这篇综述中，我们总结了 TSHR 的种系突变，重点关注 1）（儿科）患者的表型，2）潜在的基因型/表型相关性，3）对受体激活和失活的结构影响，4）对甲状腺生长的影响，以及 5）最后是 TSHR 二聚化的方面。总之，对医学和生物学数据的综合分析为理解 TSHR 的遗传缺陷和功能障碍提供了一条途径，使我们能够从分子细节和整体上了解这些缺陷和功能障碍。这些知识对于完善我们对 TSHR 基因缺陷引起的非自身免疫性疾病的认识非常重要，并且可能有助于开发补偿不受控制的甲状腺生长的药理学手段。
