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Title: Modulation of malaria phenotypes by pyruvate kinase (pklr) variants in a Thai population
Authors: Rebekah Van Bruggen
Christian Gualtieri
Alexandra Iliescu
Chalisa Louicharoen Cheepsunthorn
Punchalee Mungkalasut
Jean Francois Trape
David Modiano
Bienvenu Sodiomon Sirima
Pratap Singhasivanon
Mark Lathrop
Anavaj Sakuntabhai
Jean Francois Bureau
Philippe Gros
McGill University
Chulalongkorn University
Institut de Recherche pour le Developpement Dakar
Universita degli Studi di Roma La Sapienza
Ministere de la Sante Ouagadougou
Mahidol University
Institut Pasteur, Paris
CNRS Centre National de la Recherche Scientifique
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Dec-2015
Citation: PLoS ONE. Vol.10, No.12 (2015)
Abstract: © 2015 van Bruggen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.
ISSN: 19326203
Appears in Collections:Scopus 2011-2015

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