A mutation that produces an absolute deficiency of normal@ major globin polypeptides has been recovered from a DBA/2J male mouse. Most mice homozygous for the deficiency survived to adulthood and reproduced but were smaller at birth than their littermates and demonstrated a hypochromic, microcytic anemia with severe anisocytosis, poikilocytosis, and reticulocytosis and the presence of inclusion bodies in a high proportion of circulating erythrocytes. Mice heterozygous for the deficiency demonstrated a mild reticulocytosis but were not clinically anemic. Analysis of globin chain synthesis in vitro by 3H-leucine incorporation revealed that B-globin synthesis was nearly normal (95%) in heterozygotes and about 75% of normal in deficiency homozygotes. Molecular characterization of the mutation by restriction analysis revealed a deletion of about 3.3 kb of DNA, including regulatory sequences and all coding blocks for B-major globin. Based on genetic and hematological criteria, mice homozygous for the mutant allele, designated/fbblh-‘, rep resent the first animal model of B-thalassemia (Cooley’s anemia), a severe genetic disease of humans.

Genes for mouse CY-and fi-globins are encoded in complexes (or haplotypes) of a-like and p-like loci on chromosomes 11 (Russell and McFarland, 1974) and 7 (Hutton, 1969; Popp, 1969) respectively. Two@-globin genes are normally expressed in adult mice and are located toward the 3’end of the@ globin gene complex (Jahn et al., 1980; Edgell et al., 1981). These genes occur in polymorphic forms (Ranney et al., 1960; Russell and McFarland, 1974) that encode four types of B-globin polypeptides (Popp, 1973; Popp and Bailiff, 1973; Gilman, 1976). Mice of the Hbb” haplotype possess two genes that make an identical@ globin subunit,/3single. Mice of the Hbbd haplotype