Table 2.

Some natural and engineered RBC membrane biomechanical mutants that protect against Plasmodium infection

RBC Membrane Protein	Parasite Ligand(s)	RBC Disorder	Mutation / Perturbation	Biomechanical RBC Phenotype	Restricts P. falciparum invasion?	Protective against malaria?	References
CR1	Rh4	Knops blood group	Expression polymorphism (decreased expression)	↓deformability	Yes	Yes: P. falciparum & P. vivax	[58,60,88]
GPA	EBA175	En(a-) (MNS blood group)	GYPA null	Unknown	Yes	Unclear	[89]
GPB	EBL-1	S-s-U- (MNS blood group)	GYPB null	Unknown	Yes	Unclear	[90,91]
GPA/GPB	EBA175	Dantu Blood Group (DUP4)	GPA (extracellular)/GPB tail fusion	↑tension	Yes	Yes	[13,69]
GPC	EBA140	Gerbich-negative modification	Exon 3 deletion	↑deformabilit y; elliptocytosis	Yes	Yes	[92]
BSG	Rh5	Ok blood group;	Binding interface polymorphism	Unknown	Unknown	Unknown	[22]
	Rh5	BSG KO	CRISPR knockout	Unknown	Yes	Unknown	[61,66]
Band3/ SLC4A1 / AE1	Unknown	Southeast Asian Ovalocytosis (SAO)	Decreased Expression	↑ tension; ↓deformability	Yes	Yes: placental & cerebral malaria	[72–76]
ATP2B4	Unknown	N/A	Multiple SNPs including enhancer SNPs	High intracellular calcium; [altered] RBC hydration	Unknown	Yes: Severe malaria (GWAS & P. berghei)	[70,93–95]
PIEZO1	Unknown	Hereditary Xerocytosis	Gain of function mutations	RBC dehydration	Yes	Yes	[43,96]
Ankyrin (Ank1)	N/A	N/A	Non-functional mutants	↓ RBC deformability; ↑ osmotic fragility; ↑ clearance	Unknown	Yes: P. chabaudi (restricts invasion)	[78]
Spectrin (Sptb)	N/A	N/A	CRISPR mutagenesis of ankyrin binding site	↓deformability; ↑clearance	Unknown	Yes: P. chabaudi (invasion-independent)	[97]
Ferroportin/SLC40A1/FPN	Unknown	Hemochromatosis	Q248H mutationn	↑ osmotic fragility	Unknown	Yes: P. yoelli, P. chabaudi	[98]
	Unknown	Hemochromatosis	FPN knockout	Unknown	Unknown	No	[99]