A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis
A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis
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DOI：
10.1210/jc.2007-0366
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发表时间：
2007-07-01
影响因子：
5.8
通讯作者：
Refetoff, Samuel
中科院分区：
文献类型：
--
作者：
Grasberger, Helmut;Van Sande, Jacqueline;Refetoff, Samuel
内容：在人类甲状腺中，TSH通过与TSH受体（TSHR）结合激活cAMP和磷酸肌醇（IP）信号级联。TSHR双等位基因功能缺失突变导致TSH抵抗，临床表现为高促甲状腺素血症，甲状腺体积、甲状腺激素分泌和碘摄取正常或减少。目的：我们报道和研究一种新的家族性TSHR突变（L 653 V）。特别是，患者有显着较高的2小时放射性碘摄取和2- 24小时放射性碘摄取比与杂合子，未受影响的家庭成员相比，这表明碘捕获和有机化之间的不平衡。在转染的COS-7细胞中，突变TSHR具有正常的表面表达、基础活性和TSH结合亲和力，TSH诱导的cAMP和IP积累的EC 50值同样（2.2倍）增加，并且具有正常的最大cAMP生成。与此相反，TSH产生IP的疗效是超过7倍的突变体相比，野生型TSHR.Conclusions：我们确定和表征TSHR缺陷，优先影响IP通路，与以前报道的功能丧失突变的表型不同。结果提供了第一个在体内的TSHR/IP/Ca 2+级联调节碘化的生理作用的证据。根据系统的体外诱变研究，其他TSHR突变甚至可以导致IP信号传导的完全丧失，同时保留cAMP诱导。我们推测TSHR突变可能是原因不明的部分有机化缺陷的原因。
Context: In the human thyroid gland, TSH activates both the cAMP and inositol phosphates ( IP) signaling cascades via binding to the TSH receptor (TSHR). Biallelic TSHR loss-of-function mutations cause resistance to TSH, clinically characterized by hyperthyrotropinemia, and normal or reduced thyroid gland volume, thyroid hormone output, and iodine uptake.Objective: We report and study a novel familial TSHR mutation (L653V).Results: Homozygous individuals expressing L653V had euthyroid hyperthyrotropinemia. Paradoxically, patients had significantly higher 2-h radioiodide uptake and 2- to 24-h radioiodide uptake ratios compared with heterozygous, unaffected family members, suggesting an imbalance between iodide trapping and organification. In transfected COS-7 cells, the mutant TSHR had normal surface expression, basal activity, and TSH-binding affinity, equally (2.2-fold) increased EC50 values for TSH-induced cAMP and IP accumulation, and normal maximum cAMP generation. In contrast, the efficacy of TSH for generating IP was more than 7-fold lower with the mutant compared with wild-type TSHR.Conclusions: We identified and characterized a TSHR defect, preferentially affecting the IP pathway, with a phenotype distinct from previously reported loss-of-function mutations. Results provide the first in vivo evidence for the physiological role of the TSHR/IP/Ca2+ cascade in regulating iodination. According to systematic in vitro mutagenesis studies, other TSHR mutations can result in even complete loss of IP signaling with retained cAMP induction. We hypothesize that such TSHR mutations could be the cause in unexplained partial organification defects.