| 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. | |||||||||||