Ankyrin-1 gene exhibits allelic heterogeneity in conferring protection against malaria

Abstract

AbstractAllelic heterogeneity is a common phenomenon where a gene exhibit different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified twoAnk-1mutations, one resulted in an amino acid substitution (MRI95845), and the other a truncatedAnk-1protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection againstPlasmodium chabaudiinfections. Upon further examination, theAnk-1(MRI96570)mutation was found to inhibit intra-erythrocytic parasite maturation, whereasAnk-1(MW95845)caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between twoAnk-1mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomenon to achieve a better understanding of host-parasite interactions, which could be the basis of future studies.