A TRANSGENIC MOUSE MODEL OF HEMOGLOBIN-S ANTILLES DISEASE

Hemoglobin (Hb) S Antilles is a naturally occurring form of sickling h uman Hb but causes a more severe phenotype than Hb S. Two homozygous v iable Hb S Antilles transgene insertions from Tg58Ru and Tg98Ru mice w ere bred into MHOAH mice that express high oxygen affinity (P-50 simil ar to 24.5 mm Hg) rather than normal (P-50 similar to 40 mm Hg) mouse Hbs, The rationale was that the high oxygen affinity MHOAH Hb, the low er oxygen affinity of Hb S Antilles than Hb S (P-50 similar to 40 v 26 .5 mm Hg), and the lower solubility of deoxygenated Hb S Antilles than Hb S (similar to 11 v 18 g/dL) would favor deoxygenation and polymeri zation of human Hb S Antilles in MHOAH mouse red blood cells (RBCs). T he Tg58 x Tg98 mice produced have a high and balanced expression (simi lar to 50% each) of h alpha and h beta(S Antilles) globins, 25% to 35% of their RBCs are misshapen in vivo, and in vitro deoxygenation of th eir blood induces 30% to 50% of the RBCs to form classical looking, el ongated sickle cells with pointed ends. Tg58 x Tg98 mice exhibit retic ulocytosis, an elevated white blood cell count and lung and kidney pat hology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic interven tion of sickle cell disease. (C) 1997 by The American Society of Hemat ology.