Genetic diversity in human erythrocyte pyruvate kinase

Abstract

Previously, we have shown that pyruvate kinase, liver and red cell isoform (PKLR) deficiency protects mice in vivo against blood-stage malaria, and observed that reduced PKLR function protects human erythrocytes against Plasmodium falciparum replication ex vivo. Here, we have sequenced the human PKLR gene in 387 individuals from malaria-endemic and other regions in order to assess genetic variability in different geographical regions and ethnic groups. Rich genetic diversity was detected in PKLR, including 59 single-nucleotide polymorphisms and several loss-of-function variants (frequency 1.5%). Haplotype distribution and allele frequency varied considerably with geography. Neutrality testing suggested positive selection of the genein the sub-Saharan African and Pakistan populations. It is possible that such positive selection involves the malarial parasite.

Pyruvate Kinase Deficiency in Sub-Saharan Africa: Identification of a Highly Frequent Missense Mutation (G829A;Glu277Lys) and Association with Malaria

“…This residue is extremely well conserved and the result complies with the prediction from SIFT from a previous work [30]. Probably, the charge change (Glu is negatively whereas Lys is positively charged) at an exposed site alters the enzyme action.…”

“…The Glu277Lys mutation here identified has been previously reported in the PKLR mutation database [32] and has recently been described [30] in only two individuals: one from the Mandenka ethnic group (one of the largest ethnic groups in West Africa) and other from the Brahui ethnic group from Pakistan, showing that is also present in Middle East. Since the haplotypes that include this mutation in these two individuals are different, it was suggested that it has arisen separately.…”

“…These studies were all based in PK activity measurements. The estimated mutant allele frequencies of common variants generally vary between 0.2 and 0.8% [23] with the highest heterozygous prevalence described so far in Saudi Arabia (6%) [28], [30] and Hong Kong (3.4%) [31]. However, these last allele frequencies were not calculated from mutation genotyping but only estimated from the Beutler's screening qualitative procedure and enzyme assay [16], which result in less reliable estimates of heterozygosity.…”

The Host Genetic Diversity in Malaria Infection

“…Another enzyme associated with energy production is pyruvate kinase (PK), which is also an important factor in the susceptibility to malaria, and its deficiency has been associated with the reduced survival and increased phagocytosis of parasite-infected erythrocytes [26]. PK deficiency is the second most common cause of hereditary nonspherocytic hemolytic anemia in humans [27]. PK catalyzes the rate-limiting step of glycolysis, and the energy for erythrocytes is derived from glycolysis, as RBC lack mitochondria.…”

“…PK catalyzes the rate-limiting step of glycolysis, and the energy for erythrocytes is derived from glycolysis, as RBC lack mitochondria. The PK gene is highly pleomorphic and includes 59 SNPs and several loss-of-function variants that might be associated with decreased resistance to malaria [27]. …”