Polymorphisms associated with Plasmodium sensitivity to artemisinins
Ding XC, Beck HP, Raso G. Plasmodium sensitivity to artemisinins: magic bullets hit elusive targets. Trends Parasitol. 2011 Feb;27(2):73-81. PMID: 21169061.
Gene Polymorphisma Mutationb Effects of specific allele and comments    
pfatpase6c,d,e,f,g I89Th,i 266T>C • No significant effect knownd,h  
  H243Yj 727C>T • No significant effect knowni  
  L263Ek,l N/A • 263E engineered mutation abolishes artemisinin and artemisone inhibition of Ca2+ ATPase activity in heterologous expression experiments  
      • 263E recombinant P. falciparum show a non-significant decreased sensitivity to artemisinin, dihydroartemisinin, and artesunate in vitro  
  E431Ki,l 1291G>A • 431K, alone (one isolate) or with 632E (one isolate), shows a decreased sensitivity to artesunate in vitro    
  A623Ei 1868C>A • 623E, with 402V (one isolate) or with 431K (one isolate), shows a decreased sensitivity to artesunate in vitro  
  S769Nj,k,m 2306G>A • 769N is associated with decreased sensitivity to artemether in vitro  
      • 769N (one isolate in Africa) was found to be as susceptible as 769S to dihydroartemisinin and to artemether in vitro  
pfcrt multiplem multiple • Various mutant alleles introduced by allelic exchange in the GC03 clone and associated with chloroquine resistance induced an increased (∼4-fold) sensitivity to artemisinin and dihydroartemisinin in vitro  
  K76N, K76Id,e,f,h 228A>T, 227A>T • 76N and 76I, but not 76T, are associated with a slightly increased (∼3.5 and ∼2.5-fold, respectively) sensitivity to artemisinin in vitro  
  C350R unknown • 350R, in a pfcrt mutant background, shows a slightly (∼2-fold) decreased sensitivity to artemisinin in vitro, as compared to 350C  
pfmdr1c,d,g copy numberd,e,i,k N/A • Increased copy number is associated with a slightly (∼2-fold) decreased sensitivity to artesunate and dihydroartemisinin in vitro  
      • Increased copy number (≥3) is associated with a slightly decreased sensitivity to artesunate and artemisinin in vitro  
      • Engineered copy number decrease from 2 to 1 in a P. falciparum laboratory strain is associated with a slightly (<2-fold) increased sensitivity to artemisinin  
      • Increased copy number is associated with in vitro acquired resistance to artelinic acid and artemisinin in some, but not all P. falciparum laboratory strains tested  
      • Increased copy number was observed in an unstable P. yoelii strain resistant to artemisinin  
  N86Ye,f,h,m,n,o 256A>T • 86Y is associated with a slightly (∼2-fold) increased sensitivity to artemisinin and dihydroartemisinin in vitro  
      • 86Y is associated with a slightly (∼2-fold) increased sensitivity to artesunate and artemisinin in vitro  
  Y184Fe,f,m,n,o,p 551A>T • 184F with 1034C and/or 1042D, but not alone, is associated with a slightly (∼2-fold) increased sensitivity to artesunate and artemisinin in vitro  
  S1034Ce,f,h,m,o,p 3100A>T • 1034C together with 1042D and1246Y is associated with a slightly (∼2-fold) increased sensitivity to artemisinin in vitro  
      • 1034C, if with a single pfmdr1 copy, is associated with a slightly (∼2-fold) decreased sensitivity to artesunate in vitro  
  N1042De,f,h,m,o,p 3124A>G • 1042D together with 1034C and1246Y is associated with a slightly (∼2-fold) increased sensitivity to artemisinin in vitro  
      • 1042N is associated with a decreased sensitivity to artemisinin in vitro  
      • 1042D, if with a single pfmdr1 copy, is associated with a slightly (∼2-fold) decreased sensitivity to artesunate in vitro  
  D1246Ye,f,m,o,p 3736G>T • 1246Y alone or together with 1034C and 1042D is associated with a slightly (∼2-fold) increased sensitivity to artemisinin in vitro  
ubp-1g V739Fb,l unknown • 739F was identified in a P. chabaudi strain stably resistant to artesunate in vivo derived from a chloroquine resistant genetic background    
G7 deletion/insertionj 1390(AAT)3-4 • AAT insertion is associated with a decreased sensitivity to artesunate in vitro  
a Amino acid changes are indicated when appropriate.      
b Nucleotide changes are indicated when appropriate.
c Mutations (full length sequencing) or copy number variations in this gene have been shown to not be essential for stable artemisinin resistance in a P. chabaudi strain
d No association between alleles of this gene (full length sequencing) or this polymorphism (PCR-RFLP) and in vivo sensitivity to artemisinin in P. falciparum strains from Western Cambodia could be found
e No association between alleles of this gene (full length sequencing) or polymorphisms (PCR-RFLP) and in vivo sensitivity to artemisinin in P. falciparum strains from Western Cambodia could be found
f No association between this gene or polymorphism (full length or partial gene sequencing) and in vitro acquired resistance to artelinic acid and artemisinin in several P. falciparum laboratory strains 
g No association between alleles of this gene (full length sequencing) and in vivo resistance to AS-MF in a P. chabaudi strain
h No association between this polymorphism (PCR-RFLP) and in vitro sensitivity to artesunate and to dihydroartemisinin in P. falciparum isolates from Thailand 
I No association between this polymorphism (partial gene sequencing or real-time PCR) and in vitro acquired resistance to transient exposure to high artemisinin doses
j No association between this polymorphism (partial gene sequencing) and in vitro sensitivity to dihydroartemisinin in P. falciparum isolates from Africa 
k No association between these polymoprhisms (copy number or partial gene sequencing) and in vitro sensitivity to artesunate and artesunate treatment efficacy in Cambodia
l No association between this polymorphism (partial gene sequencing) and in vitro sensitivity to dihydroartemisinin in P. falciparum isolates from Cameroon 
m No association between this polymorphism, tested in various combinations with each other, but not individually, and in vitro sensitivity to dihydroartemisinin in laboratory-adapted P. falciparum strains
n No association between this polymorphism (partial gene sequencing) and in vitro sensitivity to artemisinin derivates in P. falciparum isolates from Cameroon
o No association between this polymorphism (primer extension) and in vitro sensitivity to artesunate and dihydroartemisinin in P. falciparum isolates from the Thai–Myanmar border 
p No association between this polymorphism (PCR-RFLP) and in vitro sensitivity to artemisinin and to dihydroartemisinin in P. falciparum isolates from the Gambia
Abbreviations: N/A, not applicable.
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