This variant has electrophoretic mobility in standard conditions identical to that of Hb S but shows a slightly higher pI than Hb S on isoelectric focusing. Heterozygous carriers of this variant hemoglobin exhibit sickling disorders. This observation may provide a clue to the unexplained clinical sickling disorders in some A/S carriers, in whom careful biochemical analyses may reveal other examples of double mutations in the beta chain. See Monplaisir et al. (1986). Pagnier et al. (1990) introduced the val23-to-ile mutation into beta-globin cDNA by site-directed mutagenesis. The beta-globin chain was synthesized using an expression vector and hemoglobin tetramers were reconstituted. When mixed with equal amounts of hemoglobin S, facilitation of polymerization was observed. Pagnier et al. (1990) listed 5 other hemoglobin variants which contain both the sickle mutation and a second amino acid substitution in the same beta chain.
Popp et al. (1997) bred 2 homozygous viable Hb S Antilles transgene insertions into a strain of mice that produce hemoglobins with a higher affinity for oxygen than normal mouse Hb. The rationale was that the high oxygen affinity hemoglobin, the lower oxygen affinity of Hb S Antilles, and the lower solubility of deoxygenated Hb Antilles than Hb S would favor deoxygenation and polymerization of human Hb S Antilles in the red cells of the high oxygen affinity mice. The investigators found that the mice produced a high and balanced expression of human alpha and human beta (S Antilles) globins, that 25 to 35% of their RBCs were misshapen in vivo, and that in vitro deoxygenation of their blood induced 30 to 50% of the RBCs to form classic elongated sickle cells with pointed ends. The mice exhibited reticulocytosis, an elevated white blood cell count, and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease.
