Generation and molecular characterization of a transgenic mouse line carrying a mutated human °39 thalassemia -globin gene

In β-thalassemias, mutations of the β-globin gene or its regulatory regions cause absence (β°) or reduced (β+) synthesis of β-globin chains, associated with a corresponding excess of the complementary α-globins. More than 200 mutations of the β-globin gene have been described. Mouse models for the different mutations causing thalassemia are very important to test in vivo the activity of novel mutation-specific therapeutic approaches. The β039-mutation is one of the most frequent in Italy and Greece. In this type of thalassemia a stop codon mutations lead to premature translation termination and to mRNA destabilization through non-sense mediated decay. Generation of a mouse that expresses such mutation could supply a model to test new compounds and therapies for these populations of patients. In this study we report the production and characterization of three transgenic mouse lines carrying a human -globin gene containing the β039 thalassemia point mutation. The major contribution of our work is the development of a transgenic TG β039 mouse, which: (a) displays a tissue specific transcription of the transgene, fully overlapping with that of the endogenous murine -globin gene; (b) as expected produces normally spliced human -globin mRNA, without production of -globin. Therefore, the TG β039 mouse might be used as an in vivo model to characterize the effects of ribosomal read-through strategies for developing experimental protocols for the treatment of 0-thalassemia caused by stop codon mutation