Generation and characterization of a transgenic mouse carrying a functional human ?-globin gene with the IVSI-6 thalassemia mutation

Mouse models that carry mutations causing thalassemia represent a suitable tool to test in vivo new mutation-specific therapeutic approaches. Transgenic mice carrying the ?-globin IVSI-6 mutation (the most frequent in Middle-Eastern regions and recurrent in Italy and Greece) are, at present, not available. We report the production and characterization of a transgenic mouse line (TG-?-IVSI-6) carrying the IVSI-6 thalassemia point mutation within the human ?-globin gene. In the TG-?-IVSI-6 mouse (a) the transgenic integration region is located in mouse chromosome 7; (b) the expression of the transgene is tissue specific; (c) as expected, normally spliced human ?-globin mRNA is produced, giving rise to ?-globin production and formation of a human-mouse tetrameric chimeric hemoglobin ? mu-globin? h u-globinand, more importantly, (d) the aberrant ?-globin-IVSI-6 RNAs are present in blood cells. The TG-?-IVSI-6 mouse reproduces the molecular features of IVSI-6 ?-thalassemia and might be used as an in vivo model to characterize the effects of antisense oligodeoxynucleotides targeting the cryptic sites responsible for the generation of aberrantly spliced ?-globin RNA sequences, caused by the IVSI-6 mutation. These experiments are expected to be crucial for the development of a personalized therapy for ?-thalassemia.