Haemoglobin C Promotes Distinct Membrane Properties in Heterozygous HbSC red Cells

Sickle Cell Disease (SCD) is one of the most common severe normal individuals. This feature causes solute loss and shrinkage, ininherited disorders. Approximately 300,000 SCD babies are born yearly, mostly in Africa, theUSA and the Caribbean, but also inNorthern Europe (Piel et al., 2013). In the UK, SCD patients number around 12–15,000 individuals (Hickman et al., 1999) making it a disease of considerable significance. There is no specific treatment. Nor is it understood why some patients have amore severe course of the disease, whereas others are mildly or even subclinically affected. Without this prognostic knowledge, it is not possible to instigate more aggressive therapies for children who will be most compromised later in life. For example, hydroxyurea therapy for these individuals may lessen later complications such as renal pathology and stroke. All SCD patients have the abnormal adult haemoglobin HbS in their red cells. All the complications of SCD follow from this. HbS has a substituted amino acid at the 6th codon of the beta chain with valine replacing glutamic acid. Homozygous SCD patients (HbSS) have two copies of this altered Hb. Heterozygous HbSC individuals have a second mutated Hb in addition, HbC in which glutamic acid at the same position is replaced with lysine. About two thirds of SCD patients are homozygous HbSS individuals but patients heterozygous for HbS and HbC (HbSC) constitute about a third of SCD cases (here termed HbSC disease), making this the second most common form of SCD (Nagel and Lawrence, 1991 & Nagel and Platt, 2001; Rees et al., 2010) and therefore representing a clinical problem of considerable impact. Although HbSC disease is common it is neglected compared to other haemoglobinopathies, such as sickle cell anaemia (HbSS) and the thalassaemias. Relatively few studies are conducted on HbSC disease, and most physiological and clinical features are inferred from studies of homozygous sickle cell anaemia (HbSS). There is considerable evidence that the two conditions are very different. Generally HbSC is less severe than HbSS, but still results in recurrent episodes of pain and progressive organ damage, resulting in a shortening of life-expectancy by 20–30 years in the northern hemisphere. Some complications are more common in HbSC than HbSS, most notably proliferative retinopathy leading to visual loss. Laboratory measurements also demonstrate the difference between the two conditions, with higher haemoglobin and lower rates of haemolysis in HbSC, and significantly lower levels of HbF. Cation homeostasis of red cells is critical in SCD. Red cells from patients have elevated cation permeability compared to those from