Molecular and cellular pathogenesis of hemoglobin SC disease.

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Abstract
Solution and cell studies were performed to ascertain why individuals with Hb SC have disease whereas those with Hb AS do not. The polymerization of deoxygenated mixtures containing sickle cell Hb (Hb S; .alpha.2.beta.26Glu .fwdarw. Val) and Hb C (.alpha.2.beta.26Glu .fwdarw. Lys) was investigated by measurements of delay times and solubilities. In mixtures containing > 40% Hb S, polymerization takes place by the same mechanism as in solutions of Hb S alone, with no evidence for independent crystallization of Hb C. A detailed comparison of Hb S/Hb C and Hb S/Hb A mixtures with identical concentrations and proportions of Hb S show that there is no significant difference in the tendency of Hb C and Hb A to copolymerize with Hb S. In 50:50 Hb S/Hb C mixtures, polymerization is about 15 times more rapid than in 40:60 Hb S/Hb A mixtures at the same total Hb concentration. Measurements on density-fractionated erythrocytes show that SC cells contain a higher total Hb concentration and a more uniform distribution of reticulocytes compared to normal (AA) or sickle trait (AS) cells. The concentration distribution for C trait (AC) cells is much closer to that of SC cells than to AS or AA cells. The presence of Hb C may result in the SC cell beginning its life with an abnormally high Hb concentration. Both the larger proportion of Hb S and the higher intracellular Hb concentration contribute to the pathogenesis of Hb SC disease.