MOUSE MODEL OF HUMAN BETA(0) THALASSEMIA - TARGETED DELETION OF THE MOUSE BETA(MAJ)-GLOBIN AND BETA(MIN)-GLOBIN GENES IN EMBRYONIC STEM CELLS

beta(0)-Thalassemia is an inherited disorder characterized by the abse nce of beta-globin polypeptides derived from the affected allele, The molecular basis for this deficiency is a mutation of the adult beta-gl obin structural gene or cis regulatory elements that control beta-glob in gene expression. A mouse model of this disease would enable the tes ting of therapeutic regimens designed to correct the defect, Here we r eport a 16-kb deletion that includes both adult beta-like globin genes , beta(maj) and beta(maj), in mouse embryonic stem cells. Heterozygous animals derived from the targeted cells are severely anemic with dram atically reduced hemoglobin levels, abnormal red cell morphology, sple nomegaly, and markedly increased reticulocyte counts, Homozygous anima ls die in utero; however, heterozygous mice are fertile and transmit t he deleted allele to progeny, The anemic phenotype is completely rescu ed in progeny derived from mating beta(0)-thalassemic animals with tra nsgenic mice expressing high levels of human hemoglobin A, The beta(0) -thalassemic mice can be used to test genetic therapies for beta(0)-th alassemia and can be bred with transgenic mice expressing high levels of human hemoglobin HbS to produce an improved mouse model of sickle c ell disease.