Toward a transgenic mouse model of sickle cell disease: Hemoglobin SAD

In order to obtain a transgenic mouse model of sickle cell disease, we have synthesized a novel human beta -globin gene, beta super(SAD), designed to increase the polymerization of the transgenic human hemoglobin S (Hb S) in vivo. beta super(SAD) ( beta super(S-Antilles-D Punjab)) includes the beta super(6)Val substitution of the beta super(S) chain, as well as two other mutations, Antilles ( beta super(23)Ile) and D Punjab ( beta super(121)Gln) each of which promotes the polymerization of Hb S in human. Hemoglobin SAD was increased to 26% in beta -thal/SAD-1 mice which exhibited: (i) abnormal erythrocytes with regard to shape and density; (ii) an enlarged spleen and a high reticulocyte count indicating an increased erythropoiesis; (iii) mortality upon hypoxia; (iv) polymerization of hemolysate similar to that obtained in human homozygous sickle cell disease; and (v) anemia and mortality during development.