Somatic mutation of TRβ can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor
Somatic mutation of TRβ can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor
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DOI：
10.1210/jc.86.11.5572
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发表时间：
2001-11-01
影响因子：
5.8
通讯作者：
Yen, PM
中科院分区：
文献类型：
--
作者：
Ando, S;Sarlis, NJ;Yen, PM
在TSH分泌性肿瘤（TSH瘤）患者中，甲状腺激素对血清TSH的抑制作用较差。TSH分泌负调节缺陷的机制尚不清楚。为了研究TR的体细胞突变导致这种缺陷的可能性，我们使用从5例手术切除的TSHoma中获得的RNA，通过RT-PCR对TR β进行了突变分析。在一个TSHoma中，我们鉴定了TR β配体结合结构域的体细胞突变，该突变导致TR β 1的密码子435（对应于TR β 2的密码子450）处的His替换为Tyr。有趣的是，这种突变与先前在甲状腺激素抵抗综合征患者中发现的两种突变（TR β H435 L和H435 Q）发生在相同的密码子中。这种突变的TR β具有受损的T-3结合和T-3介导的负调节。在共转染研究中，它还阻断了野生型TR β 2对糖蛋白激素α-亚基和TSH β报告基因的负调控。我们的研究结果表明，TR β的体细胞突变发生在TSHoma，可能是负责缺陷的负调节TSH的甲状腺激素在肿瘤中。
In patients with TSH-secreting tumors (TSHomas), serum TSH is poorly suppressed by thyroid hormone. The mechanism for this defect in negative regulation of TSH secretion is not known. To investigate the possibility of a somatic mutation of TR causing this defect, we performed mutational analysis of TR beta by RT-PCR using RNA obtained from five surgically resected TSHomas. In one TSHoma, we identified a somatic mutation in the ligand-binding domain of TR beta that caused a His to Tyr substitution at codon 435 of TR beta1 corresponding to codon 450 of TR beta2. Interestingly, this mutation occurred in the same codon as two mutations (TR beta H435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TR beta had impaired T-3 binding and T-3-mediated negative regulation. It also blocked the negative regulation by wild-type TR beta2 on glycoprotein hormone a-subunit and TSH beta reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TR beta occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor.