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Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012.

Wang Z, Shrestha S, Li X, Miao J, Yuan L, Cabrera M, Grube C, Yang Z, Cui L - Malar. J. (2015)

Bottom Line: A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo.In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.

View Article: PubMed Central - PubMed

Affiliation: Department of Entomology, The Pennsylvania State University, University Park, PA, 16802, USA. zxw11@psu.edu.

ABSTRACT

Background: The recent emergence and spread of artemisinin resistance in the Greater Mekong Subregion poses a great threat to malaria control and elimination. A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo. This study aimed to investigate the K13 polymorphisms in Plasmodium falciparum parasites from the China-Myanmar border area where artemisinin use has the longest history.

Methods: A total of 180 archived P. falciparum isolates containing 191 parasite clones, mainly collected in 2007-2012 from the China-Myanmar area, were used to obtain the full-length K13 gene sequences.

Results: Seventeen point mutations were identified in 46.1% (88/191) parasite clones, of which seven were new. The F446I mutation predominated in 27.2% of the parasite clones. The C580Y mutation that is correlated with artemisinin resistance was detected at a low frequency of 1.6%. Collectively, 43.1% of the parasite clones contained point mutations in the kelch domain of the K13 gene. Moreover, there was a trend of increase in the frequency of parasites carrying kelch domain mutations through the years of sample collection. In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).

Conclusions: This study documented the presence of mutations in the K13 gene in parasite populations from the China-Myanmar border. Mutations present in the kelch domain have become prevalent (>40%). A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.

No MeSH data available.


Related in: MedlinePlus

Frequencies of K13 mutations in 2007 to 2012. Significant increase in frequencies of mutations in the kelch domain in 2009 was noted.
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Fig3: Frequencies of K13 mutations in 2007 to 2012. Significant increase in frequencies of mutations in the kelch domain in 2009 was noted.

Mentions: The K13 protein contains a piece of Plasmodium-specific sequence and a BTB/POZ domain in the N-terminus, and a 6-blade propeller domain in the C-terminus (codons 441–725) [5]. Of the 17 mutations identified in this parasite population, six were distributed in the N-terminus in nine clones, whereas the remaining 11 occurred within the kelch propeller domain in 41.3% parasite clones. Superimposing the mutations to the predicted kelch domain structure showed that five (P441L, P443S, F446I, N458Y, C469Y) were clustered in blade I, two (L492S and F495L) in blade II, two (P574L and C580Y) in blade IV, and two (A676D and H719N) in blade VI (Figure 2). A recent multicentre clinical investigation showed that various mutations occurring in the kelch domain after position 440 are collectively associated with an increase in parasite clearance half-life [4]. When the samples were stratified by the year of collection, the frequencies of all mutations in the kelch domain, as well as all mutations in K13 gene, increased during the time 2007–2012 (Figure 3). In particular, a significant increase was observed in the frequencies of mutations in the kelch domain between 2008 and 2009 (P <0.0001). However, the frequencies of mutations in the N-terminus of K13 protein decreased over the years of collection (Figure 3).Figure 2


Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012.

Wang Z, Shrestha S, Li X, Miao J, Yuan L, Cabrera M, Grube C, Yang Z, Cui L - Malar. J. (2015)

Frequencies of K13 mutations in 2007 to 2012. Significant increase in frequencies of mutations in the kelch domain in 2009 was noted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4404080&req=5

Fig3: Frequencies of K13 mutations in 2007 to 2012. Significant increase in frequencies of mutations in the kelch domain in 2009 was noted.
Mentions: The K13 protein contains a piece of Plasmodium-specific sequence and a BTB/POZ domain in the N-terminus, and a 6-blade propeller domain in the C-terminus (codons 441–725) [5]. Of the 17 mutations identified in this parasite population, six were distributed in the N-terminus in nine clones, whereas the remaining 11 occurred within the kelch propeller domain in 41.3% parasite clones. Superimposing the mutations to the predicted kelch domain structure showed that five (P441L, P443S, F446I, N458Y, C469Y) were clustered in blade I, two (L492S and F495L) in blade II, two (P574L and C580Y) in blade IV, and two (A676D and H719N) in blade VI (Figure 2). A recent multicentre clinical investigation showed that various mutations occurring in the kelch domain after position 440 are collectively associated with an increase in parasite clearance half-life [4]. When the samples were stratified by the year of collection, the frequencies of all mutations in the kelch domain, as well as all mutations in K13 gene, increased during the time 2007–2012 (Figure 3). In particular, a significant increase was observed in the frequencies of mutations in the kelch domain between 2008 and 2009 (P <0.0001). However, the frequencies of mutations in the N-terminus of K13 protein decreased over the years of collection (Figure 3).Figure 2

Bottom Line: A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo.In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.

View Article: PubMed Central - PubMed

Affiliation: Department of Entomology, The Pennsylvania State University, University Park, PA, 16802, USA. zxw11@psu.edu.

ABSTRACT

Background: The recent emergence and spread of artemisinin resistance in the Greater Mekong Subregion poses a great threat to malaria control and elimination. A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo. This study aimed to investigate the K13 polymorphisms in Plasmodium falciparum parasites from the China-Myanmar border area where artemisinin use has the longest history.

Methods: A total of 180 archived P. falciparum isolates containing 191 parasite clones, mainly collected in 2007-2012 from the China-Myanmar area, were used to obtain the full-length K13 gene sequences.

Results: Seventeen point mutations were identified in 46.1% (88/191) parasite clones, of which seven were new. The F446I mutation predominated in 27.2% of the parasite clones. The C580Y mutation that is correlated with artemisinin resistance was detected at a low frequency of 1.6%. Collectively, 43.1% of the parasite clones contained point mutations in the kelch domain of the K13 gene. Moreover, there was a trend of increase in the frequency of parasites carrying kelch domain mutations through the years of sample collection. In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).

Conclusions: This study documented the presence of mutations in the K13 gene in parasite populations from the China-Myanmar border. Mutations present in the kelch domain have become prevalent (>40%). A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.

No MeSH data available.


Related in: MedlinePlus