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© Research
Publication : PloS one

Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in PloS one - 14 Dec 2015

van Bruggen R, Gualtieri C, Iliescu A, Louicharoen Cheepsunthorn C, Mungkalasut P, Trape JF, Modiano D, Sirima BS, Singhasivanon P, Lathrop M, Sakuntabhai A, Bureau JF, Gros P

Link to Pubmed [PMID] – 26658699

PLoS ONE 2015;10(12):e0144555

Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria.

https://www.ncbi.nlm.nih.gov/pubmed/26658699