Functional significance of the thyrotropin receptor germline polymorphism D727E
Functional significance of the thyrotropin receptor germline polymorphism D727E
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DOI：
10.1016/s0006-291x(03)00071-8
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发表时间：
2003-02-21
影响因子：
3.1
通讯作者：
Papavassiliou, AG
中科院分区：
文献类型：
--
作者：
Sykiotis, GP;Neumann, S;Papavassiliou, AG
在一个有毒的甲状腺腺瘤中，我们发现了一种新的体细胞突变，它可以结构性地激活促甲状腺激素受体(TSHR)。相邻核苷酸的两个杂合点突变导致TSHR第五个跨膜螺旋的593位密码子(A593N)上的天冬酰胺取代丙氨酸。该体细胞突变位于与胚系多态D727E相同的TSHR等位基因上。研究了TSHR单突变体A593N、D727E和双突变体A593N/D727E在瞬时转基因COS-7细胞中的功能特性。TSHR突变体A593N和A593N/D727E结构性地激活cAMP级联，而D727E突变体与野生型TSHR没有区别。令人惊讶的是，双重突变体的特定结构活性比A593N突变体低2.3倍。因此，在功能获得突变A593N存在的情况下，该多态性显著改善了G(Alphas)蛋白的激活，尽管在野生型TSHR的背景下它在功能上是惰性的。(C)2003年埃尔塞维尔科学公司(美国)。版权所有。
In a toxic thyroid adenoma we identified a novel somatic mutation that constitutively activates the thyrotropin receptor (TSHR). Two heterozygous point mutations at adjacent nucleotides led to a substitution of alanine with asparagine at codon 593 (A593N) in the fifth transmembrane helix of TSHR. This somatic mutation resided on the same TSHR allele with the germline polymorphism D727E. The functional characteristics of the single TSHR mutants A593N and D727E and of the double mutant A593N/D727E were studied in transiently transfected COS-7 cells. The TSHR mutants A593N and A593N/D727E constitutively activated the cAMP cascade, whereas the D727E mutant did not differ from the wild-type TSHR. Surprisingly, the double mutant's specific constitutive activity was 2.3-fold lower than the A593N mutant. Thus, the polymorphism significantly ameliorates G(alphas) protein activation in the presence of the gain-of-function mutation A593N, although it is functionally inert in the context of the wild-type TSHR. (C) 2003 Elsevier Science (USA). All rights reserved.