South‐east Asian ovalocytosis and the cryohydrocytosis form of hereditary stomatocytosis show virtually indistinguishable cation permeability defects

Abstract

SummaryThe hereditary stomatocytoses are a group of dominantly inherited conditions in which the osmotic stability of the red cell is compromised by abnormally high cation permeability. This report demonstrates the very marked similarities between the cryohydrocytosis form of hereditary stomatocytosis and the common tropical condition south‐east Asian ovalocytosis (SAO). We report two patients, one showing a novel cryohydrocytosis variant (Ser762Arg in SLC4A1) and a case of SAO. Both cases showed a mild haemolytic state with some stomatocytes on the blood film, abnormal intracellular sodium and potassium levels which were made markedly abnormal by storage of blood at 0°C, increased cation ‘leak’ fluxes at 37°C and increased Na+K+ pump activity. In both cases, the anion exchange function of the mutant band 3 was destroyed. Extensive electrophysiological studies comparing the cation leak and conductance in Xenopus laevis oocytes expressing the two mutant genes showed identical patterns of abnormality. These data are consistent with the cryohydrocytosis form of hereditary stomatocytosis and we conclude that the cation leak in SAO is indistinguishable from that in cryohydrocytosis, and that SAO should be considered to be an example of hereditary stomatocytosis.

Rapid Cl−/HCO3− exchange kinetics of AE1 in HEK293 cells and hereditary stomatocytosis red blood cells

“…In the latter situation, affected individuals have an increase in RBC membrane permeability to cations and in most cases a reduction of anion movements through AE1. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal Na ϩ and K ϩ fluxes (4,7,13,14,15,28,29). These data were consistent with the concept that the substitutions convert the protein from an anion exchanger into an unregulated cation channel, although, so far, no study has clearly demonstrated that the cation leaks are mediated through AE1.…”

“…11) or hereditary distal renal tubular acidosis (1). Recently, nine point mutations in the SLC4A1 gene (L687P, D705Y, R730C, S731P, H734R, E758K, R760Q, S762R, and G796R substitutions in the protein) have been reported (4,7,13,14,15,28,30). All these substitutions induce monovalent cation leaks in RBCs and are responsible for hereditary stomatocytosis (HSt) associated with hemolytic anemia (6).…”

Band 3 Missense Mutations and Stomatocytosis: Insight into the Molecular Mechanism Responsible for Monovalent Cation Leak

“…Since the initial discovery that 5 point mutations in SLC4A1 gene (responsible for L687P, D705Y, S731P, H734R, or R760Q substitutions in AE1) were associated with increased red cell Na + and K + leak [20], 4 other point mutations associated with similar red cell phenotype have been reported (G796R, E758K, S762R, and R730C) [21–24]. It has been proposed that the molecular mechanism accounting for cation leaky red cells in these hereditary stomatocytoses was a change in AE1 transport properties induced by the point mutations.…”

“…This has been extensively studied in red cells of patients heterozygous for L687P, D705Y, S731P, H734R, R760Q, and S762R AE1 mutants [20, 21]. The diffusion of K + and Na + according to their electrochemical gradients leads to osmotic fragility of the red cells.…”

“…However, the anion permeability of these cells is decreased suggesting a loss of anion exchange function of the protein [20]. Indeed, functional characterization of L687P, D705Y, R730C, S731P, H734R, S762R, and G796R mutants expressed in xenopus oocytes shows that they are no more able to exchange Cl − and HCO 3 − [21, 25]. In contrast E758K and R760Q mutants keep an anion exchange activity [24, 31].…”