Different switching patterns of beta-thalassaemic mutations at the proximal and distal CACCC box of the human HBB (beta-globin) gene

To investigate the role of proximal and distal CACCC box promoter elements in HBB function and haemoglobin switching, we analysed the effect of mutations at each element in vivo using transgenic mice as a model. We have engineered a gamma-beta minilocus construct to include the two most common naturally occurring mutations in Mediterranean populations at the proximal and distal beta CACCC box (beta-87, and beta-101 respectively) suppressing KLF1 binding. The two mutations have an effect both on the activation of HBB as well as on the silencing of HBG1 during the foetal stage of development in transgenic mice.