Diversity of the sarco/endoplasmic reticulum Ca(2+)-ATPase orthologue of Plasmodium falciparum (PfATP6).
The sarco/endoplasmic reticulum Ca(2+)-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.
Dahlström
Sabina
S
Department of Medicine, Karolinska Institutet, Stockholm, Sweden. sabina.dahlstrom@ki.se
Veiga
Maria Isabel
MI
Ferreira
Pedro
P
Mårtensson
Andreas
A
Kaneko
Akira
A
Andersson
Björn
B
Björkman
Anders
A
Gil
José Pedro
JP
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D037621:Artemisinins / Q000627:therapeutic use; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology; D007783:Lactones / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000188:drug therapy; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012717:Sesquiterpenes / Q000627:therapeutic use; D013636:Tanzania
C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D007783:Lactones; D012717:Sesquiterpenes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; C075875:artemisin