INACTIVATION OF MOUSE ALPHA-GLOBIN GENE BY HOMOLOGOUS RECOMBINATION -MOUSE MODEL OF HEMOGLOBIN-H DISEASE

We have disrupted the 5' locus of the duplicated adult alpha-globin ge nes by gene targeting in the mouse embryonic stem cells and created mi ce with alpha-thalassemia syndromes. The heterozygous knockout mice ( alpha/alpha alpha) are asymptomatic like the silent carriers in humans whereas the homozygous knockout mice (alpha/*alpha) show hemolytic a nemia, Mice with three dysfunctional alpha-globin genes generated by b reeding the 5' alpha-globin knockouts (alpha/alpha alpha) and the del etion type alpha-thalassemia mice (--/ alpha alpha) produce severe hem oglobin H disease and they die in utero. These results indicate that t he 5' alpha-globin gene is the predominant locus in mice, and suggest that it is even more dominant than its human homologue. (C) 1996 by Th e American Society of Hematology.