A humanized mouse model for a common β0-thalassemia mutation

Accurate animal models that recapitulate the phenotype and genotype of patients with β-thalassemia would enable the development of a range of possible therapeutic approaches. Here we report the generation of a mouse model carrying the codons 41–42 (−TTCT) β-thalassemia mutation in the intact human β-globin locus. This mutation accounts for approximately 40% of β-thalassemia mutations in southern China and Thailand. We demonstrate a low level of production of γ-globins from the mutant locus in day 18 embryos, as well as production of mutant human β-globin mRNA. However, in contrast to transgenic mice carrying the normal human β-globin locus, 4-bp deletion mice fail to show any phenotypic complementation of the knockout mutation of both murine β-globin genes. Our studies suggest that this is a valuable model for gene correction in hemopoietic stem cells and for studying the effects of HbF inducers in vivo in a “humanized” thalassemic environment.