title: Whole genome re-sequencing identifies a mutation in an ABC transporter (mdr2) in a Plasmodium chabaudi clone with altered susceptibility to antifolate drugs.
abstract: In malaria parasites, mutations in two genes of folate biosynthesis encoding dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) modify responses to antifolate therapies which target these enzymes. However, the involvement of other genes which modify the availability of exogenous folate, for example, has been proposed. Here, we used short-read whole-genome re-sequencing to determine the mutations in a clone of the rodent malaria parasite, Plasmodium chabaudi, which has altered susceptibility to both sulphadoxine and pyrimethamine. This clone bears a previously identified S106N mutation in dhfr and no mutation in dhps. Instead, three additional point mutations in genes on chromosomes 2, 13 and 14 were identified. The mutated gene on chromosome 13 (mdr2 K392Q) encodes an ABC transporter. Because Quantitative Trait Locus analysis previously indicated an association of genetic markers on chromosome 13 with responses to individual and combined antifolates, MDR2 is proposed to modulate antifolate responses, possibly mediated by the transport of folate intermediates.
authors.affiliation: Centro de Malaria e Outras Doenças Tropicais/IHMT/UEI Biologia Molecular, Universidade Nova de Lisboa, Rua da Junqueira 96, 1349-008 Lisbon, Portugal. amartinelli@ihmt.unl.pt
authors.forename: Axel
authors.initials: A
authors.lastname: Martinelli
authors.forename: Gisela
authors.initials: G
authors.lastname: Henriques
authors.forename: Pedro
authors.initials: P
authors.lastname: Cravo
authors.forename: Paul
authors.initials: P
authors.lastname: Hunt
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D019450:Genes, MDR; D051379:Mice; D008808:Mice, Inbred CBA; D020125:Mutation, Missense; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine