Erythrocytes carrying mutations in spectrin and protein 4.1 show differing sensitivities to invasion by Plasmodium falciparum.
The role of the erythrocyte skeleton in the invasion process of Plasmodium falciparum was evaluated using genetically variant erythrocytes containing well-defined molecular defects in alpha spectrin (alpha Sp) or protein 4.1 from eight unrelated families. Invasion into red cells from subjects of three black families with hereditary pyropoikilocytosis (HPP) due to inheritance of alpha I/74 mutant spectrin was significantly reduced in cells both from the patients and from the relatives of these who carried asymptomatic hereditary elliptocytosis (HE). Likewise, reduced invasion was also seen in red cells from two families with HE in which the alpha I/65 variant spectrin was present. Resistance to invasion was not absolute in any sample and varied between 38% and 71% of that seen in normal cells. The decreased invasion correlated with the percentage of spectrin dimers present within the membrane of variant cells. In contrast, invasion into elliptocytes from three families that had a partial deficiency in protein 4.1 (HE/4.1+) but a normal percentage of spectrin dimers was either unchanged or increased. The precise mechanism and molecular basis behind the reduced invasion into HPP and HE red cells bearing Sp alpha I domain variants remains to be elucidated but might relate to alterations in merozoite/red cell-receptor interactions and/or merozoite endocytosis. The occurrence of elliptocytosis with spectrin defects (in particular, Sp alpha I/65 and Sp alpha I/46 variants in West Africa) suggests that these mutations of the alpha Sp gene could be related to some protection against malaria.
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D000745:Anemia, Hemolytic, Congenital / Q000235:genetics / Q000469:parasitology*; D000818:Animals; D044383:Black People / Q000235:genetics; D003598:Cytoskeletal Proteins; D004198:Disease Susceptibility; D004910:Erythrocyte Membrane / Q000737:chemistry; D004913:Erythrocytes, Abnormal / Q000469:parasitology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009479:Neuropeptides; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D011487:Protein Conformation; D013049:Spectrin / Q000737:chemistry / Q000235:genetics*
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; C028841:erythrocyte membrane band 4.1 protein; C120557:erythrocyte membrane protein band 4.1-like 1; D013049:Spectrin