The genetic basis of resistance to anticoagulants in rodents
The genetic basis of resistance to anticoagulants in rodents
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DOI：
10.1534/genetics.104.040360
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发表时间：
2005-08-01
期刊：
影响因子：
3.3
通讯作者：
M端ller, CR
中科院分区：
文献类型：
--
作者：
Pelz, HJ;Rost, S;M端ller, CR
抗凝血剂化合物，即4-羟基香豆素（如华法林、溴二酮）或茚-1,3-二酮（如地伐西酮、氯伐西酮）的衍生物，已在世界范围内作为灭鼠剂使用了50多年。这些化合物通过抑制维生素K还原酶反应（VKOR）来抑制血液凝固。许多国家都报道了抗凝药抗性啮齿动物种群，这给害虫防治带来了相当大的问题。抗性是作为常染色体显性性状传播的，尽管直到最近，基本的基因突变是未知的。在这里，我们报告了在棕色大鼠和家鼠的抗性实验室菌株以及来自欧洲不同地点的野生棕色大鼠中鉴定出的8种不同的VKORC1基因突变，其中5种突变仅影响两种氨基酸（Tyr139Cys, Tyr139Ser， Tyr139Phe和Leu128Gln， Leu128Ser）。通过在HEK293细胞中重组表达VKORC1构建物，我们证明Tyr139突变在不同程度上赋予了对warlarin的抗性，而其他突变也显著降低了VKOR活性。我们的数据有力地证明，在棕色大鼠中至少有7个独立的突变事件，在小鼠中有2个。他们认为VKORC1的突变是野生啮齿动物抗凝血药物耐药性的遗传基础，尽管突变本身并不能解释已报道的抗凝血药物耐药性的所有方面。我们假设这些突变除了产生VKORC1蛋白的结构变化外，还可能诱导代偿机制来维持血液凝固。我们的发现为基于dna的啮齿动物抗凝血药物耐药性现场监测提供了基础。
Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.g., warfarin, bromadiolone) or indane-1,3-dione (e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for > 50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warlarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents.