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

Abstract

BackgroundPyruvate kinase (PK) deficiency, causing hemolytic anemia, has been associated to malaria protection and its prevalence in sub-Saharan Africa is not known so far. This work shows the results of a study undertaken to determine PK deficiency occurrence in some sub-Saharan African countries, as well as finding a prevalent PK variant underlying this deficiency.Materials and MethodsBlood samples of individuals from four malaria endemic countries (Mozambique, Angola, Equatorial Guinea and Sao Tome and Principe) were analyzed in order to determine PK deficiency occurrence and detect any possible high frequent PK variant mutation. The association between this mutation and malaria was ascertained through association studies involving sample groups from individuals showing different malaria infection and outcome status.ResultsThe percentage of individuals showing a reduced PK activity in Maputo was 4.1% and the missense mutation G829A (Glu277Lys) in the PKLR gene (only identified in three individuals worldwide to date) was identified in a high frequency. Heterozygous carrier frequency was between 6.7% and 2.6%. A significant association was not detected between either PK reduced activity or allele 829A frequency and malaria infection and outcome, although the variant was more frequent among individuals with uncomplicated malaria.ConclusionsThis was the first study on the occurrence of PK deficiency in several areas of Africa. A common PKLR mutation G829A (Glu277Lys) was identified. A global geographical co-distribution between malaria and high frequency of PK deficiency seems to occur suggesting that malaria may be a selective force raising the frequency of this 277Lys variant.

Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations

“…Peripheral whole blood samples were collected from unrelated individuals (mainly children under or equal to 15 years-old; only 7 adults with more or equal than 16 years-old in the asymptomatic group from Maputo, Mozambique) from two malaria endemic sub-Saharan African areas, Angola (N = 124 from Luanda, Machado et al, 2010) and Mozambique (N = 250 from Maputo, Machado et al, 2010Machado et al, , 2012 and N = 13 from Manhiça district, Marques et al, 2005).…”

“…Same criteria were used to group the 263 isolates from Mozambique: 93 SM, 150 UM and 20 AI (Marques et al, 2005;Machado et al, 2010Machado et al, , 2012.…”

“…As reported before in Marques et al (2005) and Machado et al (2010Machado et al ( , 2012, the human isolates collection was approved by Ministry of Public Health of Angola and Mozambique and by the local Ethical Committees at the institutions involved in those studies. Informed consent was obtained from all individuals.…”

“…Humphries et al (1999a) reported that -5G and associated haplotypes were found to be in linkage disequilibrium (LD) with an intragenic polymorphism at nucleotide 2262 in intron 5 (Arya et al, 1997), which could be indicative of a common ancestral origin. Schneider et al (1998) suggests that the high incidence of these TPI1 promoter polymorphisms in African-origin populations, associated to a reduced enzyme activity, may have resulted from some selective advantage for survival similarly to glucose-6-phosphate dehydrogenase (G6PD) deficient variants (Luzzatto, 2006) and pyruvate kinase (PK) deficient variants (Machado et al, 2010(Machado et al, , 2012 and hemoglobin polymorphisms (HbS) (Fleming et al, 1979). These are reminiscent examples of genetic diversity in African populations associated to protection of human host against malaria infection and resulting from the selective pressure that malaria has imposed to human populations.…”

Coinheritance of hereditary ellyptocytosis, pyruvate kinase, and glucose‐6‐phosphate dehidrogenase mutations. A rare anemia diagnostic paradigm

“…The PKLR mutation c.829G>A (p.Glu277Lys), present in heterozygous condition in the mother and her sons, has been previously reported in the PKLR mutation database 7 and was described in a high frequency in sub-Saharan African areas but also in Pakistan. 8,9 As the haplotypes that include this mutation in these two populations are different, it is assumed that they have arisen separately.…”