Polymorphisms associated
with Plasmodium sensitivity to artemisinins |
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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. |
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Gene |
Polymorphisma |
Mutationb |
Effects of specific allele
and comments |
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� |
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pfatpase6c,d,e,f,g |
I89Th,i |
266T>C |
� No
significant effect knownd,h |
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H243Yj |
727C>T |
� No significant effect knowni |
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L263Ek,l |
N/A |
� 263E engineered mutation abolishes artemisinin and artemisone
inhibition of Ca2+ ATPase activity in heterologous expression experiments |
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� 263E recombinant P. falciparum show a non-significant decreased sensitivity to
artemisinin, dihydroartemisinin, and artesunate in vitro |
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E431Ki,l |
1291G>A |
� 431K, alone (one isolate) or with 632E (one isolate), shows a
decreased sensitivity to artesunate in vitro |
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� |
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A623Ei |
1868C>A |
� 623E, with 402V (one isolate) or with 431K (one isolate),
shows a decreased sensitivity to artesunate in vitro |
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S769Nj,k,m |
2306G>A |
� 769N is associated with decreased sensitivity to artemether in
vitro |
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� 769N (one isolate in Africa) was found to be as susceptible as
769S to dihydroartemisinin and to artemether in vitro |
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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 |
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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 |
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C350R |
unknown |
� 350R, in a pfcrt mutant background, shows a slightly
(∼2-fold) decreased sensitivity to artemisinin in vitro, as compared to
350C |
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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 |
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� Increased copy number (≥3) is associated with a slightly
decreased sensitivity to artesunate and artemisinin in vitro |
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� 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 |
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� 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 |
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� Increased copy number was observed in an unstable P. yoelii
strain resistant to artemisinin |
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N86Ye,f,h,m,n,o |
256A>T |
� 86Y is associated with a slightly (∼2-fold) increased
sensitivity to artemisinin and dihydroartemisinin in vitro |
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� 86Y is associated with a slightly (∼2-fold) increased
sensitivity to artesunate and artemisinin in vitro |
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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 |
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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 |
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� 1034C, if with a single pfmdr1 copy, is associated with a
slightly (∼2-fold) decreased sensitivity to artesunate in vitro |
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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 |
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� 1042N is associated with a decreased sensitivity to
artemisinin in vitro |
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� 1042D, if with a single pfmdr1 copy, is associated with a
slightly (∼2-fold) decreased sensitivity to artesunate in vitro |
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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 |
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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 |
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G7 |
deletion/insertionj |
1390(AAT)3-4 |
� AAT insertion is associated with a decreased sensitivity to
artesunate in vitro |
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a Amino acid
changes are indicated when appropriate. |
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b Nucleotide
changes are indicated when appropriate. |
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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 |
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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 |
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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 |
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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 |
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g No association between alleles of this
gene (full length sequencing) and in vivo resistance to AS-MF in a P. chabaudi strain |
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h No
association between this polymorphism (PCR-RFLP) and in
vitro sensitivity to artesunate and to dihydroartemisinin in P. falciparum isolates
from Thailand |
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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 |
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j No
association between this polymorphism (partial gene sequencing) and in
vitro sensitivity to dihydroartemisinin in P.
falciparum isolates from Africa |
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k No association between these
polymoprhisms (copy number or partial gene sequencing) and in
vitro sensitivity to artesunate and artesunate treatment efficacy in
Cambodia |
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l No
association between this polymorphism (partial gene sequencing) and in
vitro sensitivity to dihydroartemisinin in P.
falciparum isolates from Cameroon |
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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 |
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n No
association between this polymorphism (partial gene sequencing) and in
vitro sensitivity to artemisinin derivates in P.
falciparum isolates from Cameroon |
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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 |
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p No association between this polymorphism
(PCR-RFLP) and in vitro sensitivity to artemisinin and to
dihydroartemisinin in P. falciparum isolates from the Gambia |
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Abbreviations: N/A, not applicable. |
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