Diversity of the sarco/endoplasmic reticulum Ca2+-ATPase orthologue of Plasmodium falciparum (PfATP6)
Diversity of the sarco/endoplasmic reticulum Ca2+-ATPase orthologue of Plasmodium falciparum (PfATP6)
复制标题
DOI：
10.1016/j.meegid.2008.02.002
复制
发表时间：
2008-05-01
影响因子：
3.2
通讯作者：
Gil, Jose Pedro
中科院分区：
文献类型：
--
作者：
Dahlstrom, Sabina;Veiga, Maria Isabel;Gil, Jose Pedro
恶性疟原虫的肌浆/内质网 Ca2(+)-ATP 酶同源物 (PfATP6) 被认为参与青蒿素的作用和耐药机制，而青蒿素是基于青蒿素的联合疗法 (ACT) 的主要成分。在之前的研究中，仅在临床样本和现场分离物中描述了六种单核苷酸多态性（SNP）。我们的目的是对大量不同地理来源的临床样本进行测序，以进一步探索 PfATP6 的天然多样性。我们对来自 17 个国家（主要是桑给巴尔和坦桑尼亚）的 388 个样本中 PfATP6 的 3 个基因区域进行了测序，并鉴定了 33 个 SNP，其中 29 个是非同义的，4 个是同义的。据我们所知，其中 29 个 SNP 以前从未被描述过。桑给巴尔和坦桑尼亚高频率发现了三种突变； E431K、N569K 和 A630S 分别存在于 31%（95% CI，26-37%）、36%（95% CI，30-42%）和 2%（95% CI，1-5%）的桑给巴尔样本中，以及 39%（95% CI，29-51%）、29%（95% CI，坦桑尼亚大陆样本的 16-45%）和 7%（95% CI，1-22%）。在第 263 位没有发现变异，这表明与青蒿素与 PfATP6 的结合有关，而在第 769 位则没有发现变异，这被认为与体外对蒿甲醚的敏感性降低有关。在三个遗传区域之间观察到多样性的显着差异。总之，我们的研究结果表明 PfATP6 是一个比之前证明的更加多样化的基因。这种自然变异可能构成青蒿素驱动的耐药寄生虫逐步选择的起点。 (c) 2008 Elsevier B.V. 保留所有权利。
The sarco/endoplasmic reticulum Ca2(+)-ATPase orthologue of Plasmodium falciparum (PfATP6) has been suggested to be involved in the mechanism of action and resistance to artemisinins, the main constituent of artemisinin-based combination therapy (ACT). In previous studies only six single-nucleotide polymorphisms (SNPs) have been described in clinical samples and field isolates. Our aim was to sequence a large number of clinical samples with different geographical origins to further explore the natural diversity of PfATP6. We sequenced three genetic regions of PfATP6 in 388 samples from 17 countries, mainly Zanzibar and Tanzania, and identified 33 SNPs, of which 29 were non-synonymous and 4 synonymous. To our knowledge 29 of these SNPs have not been described previously. Three mutations were found in high frequency in Zanzibar and Tanzania; E431K, N569K and A630S were present in respectively 31% (95% CI, 26-37%), 36% (95% CI, 30-42%), and 2% (95% CI, 1-5%) of Zanzibar samples and in 39% (95% CI, 29-51%), 29% (95% CI, 16-45%) and 7% (95% CI, 1-22%) of the Tanzania Mainland samples. No variation was found in position 263, suggested to be involved in artemisinin binding to PfATP6, or in position 769, proposed to be related to decreased sensitivity to artemether in vitro. A considerable difference in diversity was observed between the three genetic regions. In conclusion our findings show that PfATP6 is a more diverse gene than previously demonstrated. This natural variation may constitute a starting ground for artemisinin-driven progressive selection of resistant parasites. (c) 2008 Elsevier B.V. All rights reserved.