Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum.
The determinant of chloroquine resistance (CQR) in a Plasmodium falciparum cross was previously mapped by linkage analysis to a 36 kb segment of chromosome 7. Candidate genes within this segment have been previously shown to include two genes, cg2 and cg1, that have complex polymorphisms linked to the CQR phenotype. Using DNA transfection and allelic exchange, we have replaced these polymorphisms in CQR parasites with cg2 and cg1 sequences from chloroquine sensitive parasites. Drug assays of the allelically-modified lines show no change in the degree of CQR, providing evidence against the hypothesis that these polymorphisms are important to the CQR phenotype. Similarly, no change was found in the degree to which verapamil or other chloroquine sensitizers reverse CQR in the transformants. These results and the high though not complete degree of association of CQR with cg2 and cg1 polymorphisms in field isolates suggest involvement of another nearby gene in the P. falciparum CQR mechanism.
Fidock
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DA
National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive MSC 0425, Bethesda, MD 20892-0425, USA.
Nomura
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Cooper
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Su
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Talley
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Wellems
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D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D017125:Genes, Protozoan; D006801:Humans; D008288:Malaria / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D014162:Transfection; D014170:Transformation, Genetic
D000962:Antimalarials; C109423:CG1 protein, Plasmodium falciparum; C109422:CG2 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine