A chromosomal rearrangement in a P. falciparum histidine-rich protein gene is associated with the knobless phenotype.
The significant morbidity and mortality associated with Plasmodium falciparum malaria results, in part, from the sequestration of parasitized erythrocytes in postcapillary venules, which may protect the parasite from splenic clearance and contribute to the pathogenesis of cerebral malaria. This sequestration has been linked to the expression of parasite-induced knob structures on the surface of the infected erythrocyte which mediate the cytoadherence phenomenon. While knobs are necessary for cytoadherence, they are not sufficient, requiring both parasite- and host-encoded proteins. Spontaneous mutants of P. falciparum have been isolated from in vitro cultures which lack the ability to express knobs and fail to cytoadhere. A histidine-rich protein has been described which is associated with the knobby phenotype and may be a constituent of the knob. We now report the isolation of complementary DNA clones for a knob-associated histidine-rich protein (KAHRP) and demonstrate that in knobless mutants the gene for this protein has undergone a rearrangement, resulting in a deletion in the 3' coding sequence. Moreover, the chromosome to which the KAHRP gene maps is rearranged in these mutants, producing a telomeric location of the truncated gene. These observations explain the loss of expression of the messenger RNA and protein in such mutants and may explain the loss of the knob itself. The implications for the generation of spontaneous mutations in the parasite by this novel mechanism are discussed.
D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D004262:DNA Restriction Enzymes; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D010963:Plasmodium falciparum / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D015800:Protozoan Proteins; D011995:Recombination, Genetic; D000099053:Histidine-Rich Glycoprotein
D010455:Peptides; D011506:Proteins; D015800:Protozoan Proteins; D000099053:Histidine-Rich Glycoprotein; C042968:knob protein, Plasmodium falciparum; D004247:DNA; D004262:DNA Restriction Enzymes