Cellular pathogenesis of HbSC disease.

Sickle cell patients with HbSC genotype represent the second commonest form of sickle cell disease (SCD) amongst people of African origin. HbSC cells are markedly shrunken. Although containing only about half the amount of HbS as red cells from homozygous HbSS patients, HbS in HbSC cells will still polymerise on deoxygenation-which underlies the various clinical complications. The cause of dehydration is increased cation permeability mediated via three main transport systems: Piezo1, the Gárdos channel and the KCl cotransporter (KCC). Channel activity in HbSC cells is reduced in comparison with those homozygous for HbS. By contrast, KCC activity is higher, especially and unusually in the denser red cell fractions. Inhibition of KCC activity shifts the density of HbSC reticulocytes to less dense fractions. In HbSC patients, clinical severity correlates with KCC activity. Inhibition of KCC activity in HbSC patients therefore remains an obvious therapeutic strategy but has not been vigorously pursued. Clinical trials involving HbSC patients are few. Recent advances in culturing immortalized red cell lines containing the HbSC mutation and the recent generation of transgenic HbSC mice models offer the prospect of much needed impetus to facilitate research into this disease and into developing cost-effective chemotherapeutic interventions.