Prevalence of the Dihydrofolate Reductase Asn-108 Mutation as the Basis for Pyrimethamine-Resistant Falciparum Malaria in the Brazilian Amazon

Peterson, David S.; Santi, Sílvia Maria Di; Póvoa, Marinete Marins; Calvosa, Vanja Suely Pachiano; Rosário, Virgílio Estólio do; Wellems, Thomas E.

doi:10.4269/ajtmh.1991.45.492

Cited by 85 publications

(49 citation statements)

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“…The prevalence of Ala-436 and Gly-437 mutations was tested by specific-mutation enzyme analysis; the digestion of the amplified DHPS domain (Figure 4a) by Ava II shows that Gly-437 was present in all isolates, showing the same profile as that of the 3D7 mutant reference clone (Figure 4b, lane 11). The DHFR and DHPS mutations prevalent in Venezuela, in comparison with previous reports from areas with a high rate of SP failure in Bolivia, Mali, Kenya, Malawi, 9 Brazil, 21 Papua New Guinea, 22 and Cameroon, 23,24 are shown in Table 1.…”

Section: Resultsmentioning

confidence: 91%

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Urdaneta¹,

Plowe²,

Goldman³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The present study was designed to characterize mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum in the Bolivar region of Venezuela, where high levels of clinical resistance to sulfadoxine-pyrimethamine (SP, Fansidar; F. Hoffman-La Roche, Basel, Switzerland) has been documented. We used a nested mutation-specific polymerase chain reaction and restriction digestion methods to measure 1) the prevalence of DHFR mutations at 16, 50, 51, 59, 108, and 164 codon positions, and 2) the prevalence of mutations in the 436, 437, 581, and 613 codon sites in DHPS gene. In the case of the DHFR gene, of the 54 parasite isolates analyzed, we detected the presence of Asn-108 and Ile-51 in 96% of the isolates and Arg-50 mutation in 64% of the isolates. Each of these mutations has been associated with high level of resistance to pyrimethamine. Only 2 samples (4%) showed the wild type Ser-108 mutation and none showed Thr-108 and Val-16 mutations that are specific for resistance to cycloguanil. In the case of DHPS gene, we found a mutation at position 437 (Gly) in 100% of the isolates and Gly-581 in 96% of the isolates. The simultaneous presence of mutations Asn-108 and Ile-51 in the DHFR gene and Gly-437 and Gly-581 in the DHPS gene in 96% of the samples tested suggested that a cumulative effect of mutations could be the major mechanism conferring high SP resistance in this area.

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Section: Resultsmentioning

confidence: 91%

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Urdaneta¹,

Plowe²,

Goldman³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The final volume in all the amplifications was adjusted at 25 L using 200 M of each dNTP, 1 M of each primer, 2.5 U of Taq DNA polymerase (Promega) per reaction, and 1.5 mM of MgCl 2 in the enzyme buffer (50 mM KCl, 10 mM Tris-HCl, pH 9.0, 0.1% Triton X-100). 14,15 The PCR products for the two markers were subjected to electrophoresis in a 2.0% agarose gel stained with an aqueous solution of 0.5 g/mL ethidium bromide and analyzed with the One-Dscan one-dimensional electrophoresis program (Scanalytics, Fairfax, VA).…”

mentioning

confidence: 99%

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Gómez¹,

Chaparro²,

Rubiano³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Colombian field isolates of Plasmodium falciparum were analyzed for genetic diversity. Fifty-three samples were collected as thick smears from patients living in Panguí, an isolated area with low migration. While the samples were being collected, Panguí was experiencing an epidemic outbreak of malaria. The samples were typified using nested polymerase chain reaction (PCR) amplification of block 2 of the merozoite surface protein 1 (MSP1) gene and nested PCR with mutation-specific primers for position 108 of the dihydrofolate reductase enzyme gene. The results for the circulating population of parasites in Panguí show low diversity-four allelic forms-using MSP1 as a marker, a fact that contrasts with data reported for certain Asian and African zones. A high percentage of mixed infections was observed, as was high complexity of the infection. No differential distributions were found for any allelic type.

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“…Subsequently, the same polymorphism in P. falciparum dhfr was found in a number of pyrimethamine-resistant and -sensitive clones, both from the laboratory and the field, and additional mutations in codons 51 and 59 were suggested to underlie increased resistance to the drug (Cowman et al 1988;Peterson et al 1988Peterson et al , 1991. It is now well established that high-level pyrimethamine resistance results from the accumulation of mutations in the dhfr gene, principally at codons 108, 59 and 51, giving rise to S108N, C59R and N51I.…”

Section: Discovery Of Drug Resistance Markers Through Investigation Omentioning

confidence: 75%

Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance

Mwangi

Ranford-Cartwright

2013

Parasitology

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Mwangi, J.M., and Ranford-Cartwright, L.C. (2013) Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance. Parasitology, 140 (12 The biggest threat to the war on malaria is the continued evolution of drug resistance by the parasite. Resistance to almost all currently available antimalarials now exists in Plasmodium falciparum which causes the most suffering among all human malaria parasites. Monitoring of antimalarial efficacy and the development and subsequent spread of resistance has become an important part in the treatment and control of malaria. With recent reports of reduced efficacy of artemisinin, the current recommended treatment for uncomplicated malaria, there is urgent need for better methods to recognize and monitor drug resistance for effective treatment. Molecular markers have become a welcome addition to complement the more laborious and costly in vitro and in vivo methods that have traditionally been used to monitor drug resistance. However, there are currently no molecular markers for resistance to some antimalarials. This review highlights the role of the various genetic and genomic approaches that have been used in identifying the molecular markers that underlie drug resistance in P. falciparum. These approaches include; candidate genes, genetic linkage and genome-wide association studies. We discuss the requirements and limitations of each approach and use various examples to illustrate their contributions in identifying genomic regions of the parasite associated with antimalarial drug responses.

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Prevalence of the Dihydrofolate Reductase Asn-108 Mutation as the Basis for Pyrimethamine-Resistant Falciparum Malaria in the Brazilian Amazon

Cited by 85 publications

References 0 publications

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance

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