A hypothesis of the erythrocyte rigidity in Southeast Asian ovalocytosis

Abstract

Erythrocytes in Southeast Asian ovalocytosis are poorly deformable, due to a deletion of nine amino acids in Band 3, a transmembrane glycoprotein in- volved in the transport of tissue CO2 to lungs and mediating an obligatory one-to-one anion exchange of Clor HCOby alternating between an outward- facing (Band 3o) and an inward-facing (Band 3i) conformation (1). The phenotype is autosomal dominant, occurs only in the heterozygous state, and is asymptomatic. It is prevalent in malaria endemic regions of Southeast Asia and of Papua New Guinea, and appears to protect against heavy infections and cerebral malaria. The deletion in- activates the anion transport and occurs at the boundary of the Band 3 cytoplasmic and trans- membrane domains (positions 400 and 408), which is thought to connect the two domains flexibly. Explications of the erythrocyte rigidity have fo- cussed on the view that the erythrocyte deforma- bility, namely the property to rapidly deform and revert to its resting biconcave disc shape after a transient mechanical stress, is due to the mem- brane skeleton elasticity. They hypothesize that the normal contraction and extension of the membrane skeleton is prevented by the deleted Band 3 due to either its conformation, stiffness, state of association or binding to peripheral pro- teins. A mechanism of erythrocyte shape control has been previously proposed in which Band 3 plays a central role (2). Specifically, decrease and in- crease of the Band 3o/Band 3i ratio contract and relax the membrane skeleton, thus favoring echinocytosis and stomatocytosis, respectively. The equilibrium Band 3o/Band 3i ratio is deter- mined by the equilibrium Donnan ratio of anions and proton, increasing with it (r ¼Cl � /Cl � ¼HCO � / HCO � ¼H þ /H þ ). The mechanism would explain the erythrocyte rigidity since the inability of the deleted Band 3 to transport anions and to flex would prevent conformational changes or defor- mations of the membrane skeleton. It would also explain the erythrocyte resistance to endocytosis by stomatocytogenic drugs. Indeed, stomatocyto- genic and echinocytogenic drugs and amphiphilic compounds appear to act by altering the Band 3 conformation since they inhibit the Band 3 anion transport and that several of them have been shown to inhibit and alter the erythrocyte shape concomitantly. Moreover, some Band 3 substrates and specific anion transport inhibitors are echino- cytogenic. If valid, the mechanism would imply that the membrane skeleton is inelastic and that erythrocyte deformations in blood circulation oc- cur by conformational changes of Band 3 produced directly or indirectly by mechanical and chemical stresses.