LETHAL THALASSEMIA AFTER INSERTIONAL DISRUPTION OF THE MOUSE MAJOR ADULT BETA-GLOBIN GENE

Thalassemias are hereditary anemias caused by mutations that disturb the normal 1:1 balance of alpha- and beta-globin chains that form hemoglobin. We have disrupted the major adult beta-globin gene (b1) in mouse embryonic stem cells by using homologous recombination to insert selectable sequences into the gene. Mice homozygous for this insertional disruption of the b1 gene (Hbb(th-2)/Hbb(th-2)) are severely anemic and die perinatally. In contrast, almost-equal-to 60% of mice homozygous for deletion of the same gene (Hbb(th-1)/Hbb(th-1)) survive to adulthood and are much less anemic [Skow, L. C., Burkhart, B. A., Johnson, F. M., Popp, R. A., Goldberg, S. Z., Anderson, W. F., Barnett, L. B. & Lewis, S. E. (1983) Cell 34, 1043-1052]. These different phenotypes have implications for the control of beta-globin gene expression.