Pyruvate kinase deficiency in sub-Saharan Africa: identification of a highly frequent missense mutation (G829A;Glu277Lys) and association with malaria.
BACKGROUND
Pyruvate 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.


METHODS
Blood 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.


RESULTS
The 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.


CONCLUSIONS
This 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.
Centro de Malária e outras Doenças Tropicais, Unidade de Parasitologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal.
Patrícia
P
Machado
Licínio
L
Manco
Cláudia
C
Gomes
Cristina
C
Mendes
Natércia
N
Fernandes
Graça
G
Salomé
Luis
L
Sitoe
Sérgio
S
Chibute
José
J
Langa
Letícia
L
Ribeiro
Juliana
J
Miranda
Jorge
J
Cano
João
J
Pinto
António
A
Amorim
Virgílio E
VE
do Rosário
Ana Paula
AP
Arez
D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000368:Aged; D000740:Anemia / Q000150:complications; D002648:Child; D002675:Child, Preschool; D019353:Endemic Diseases; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005843:Geography; D006801:Humans; D007223:Infant; D008288:Malaria / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics* / Q000469:parasitology; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D010961:Plasmodium; D018807:Polymorphism, Single-Stranded Conformational; D017433:Protein Structure, Secondary; D011770:Pyruvate Kinase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D055815:Young Adult
D011770:Pyruvate Kinase