A MOUSE MODEL FOR BETA(0)-THALASSEMIA

We have used a ''plug and socket'' targeting technique to generate a mouse model of beta(0)-thalassemia in which both the b1 and b2 adult globin genes have been deleted, Mice homozygous for this deletion (Hbb(th-3)/Hbb(th-3)) die perinatally, similar to the most severe form of Cooley anemia in humans, Mice heterozygous for the deletion appear normal, but their hematologic indices show characteristics typical of severe thalassemia, including dramatically decreased hematocrit, hemoglobin, red blood cell counts, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration, as well as dramatically increased reticulocyte counts, serum bilirubin concentrations, and red cell distribution widths. Tissue and organ damage typical of beta-thalassemia, such as bone deformities and splenic enlargement due to increased hematopoiesis, are also seen in the heterozygous animals, as is spontaneous iron overload in the spleen, liver, and kidneys, The mice homozygous for the b1 and b2 deletions should be of great value in developing therapies for the treatment of thalassemias in utero. The heterozygous animals will be useful for studying the pathophysiology of thalassemias and hale the potential of generating a model of sickle cell anemia when mated with appropriate transgenic animals.