Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb beta(s)-globin yeast artificial chromosome: A mouse model of sickle cell anemia

Sickle cell anemia (SCA) and thalassemia are among the most common genetic diseases worldwide. Current approaches to the development of murine models of SCA involve the elimination of functional murine alpha- and beta-globin genes and substitution with human alpha and beta(s) transgenes. Recently, t wo groups have produced mice that exclusively express human HbS. The transg enic lines used in these studies were produced by coinjection of human alph a-, gamma-, and beta-globin constructs. Thus, all of the transgenes are int egrated at a single chromosomal site. Studies in transgenic mice have demon strated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developme ntal and stage-restricted expression of the genes, As the cis-acting sequen ces that participate in activation and silencing of the gamma- and beta-glo bin genes are not fully defined, murine models that preserve the normal str ucture of the locus are likely to have significant advantages for validatin g future therapies for SCA. To produce a model of SCA that recapitulates no t only the phenotype, but also the genotype of patients with SCA, we have g enerated mice that exclusively express HbS after transfer of a 240-kb beta( s) yeast artificial chromosome. These mice have hemolytic anemia, 10% irrev ersibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of SCA.