Novel metabolism of several beta zero-thalassemic beta-globin mRNAs in the erythroid tissues of transgenic mice

Abstract

Mice that are transgenic for human beta zero-thalassemic beta-globin alleles were generated in order to study how beta zero-thalassemic mutations affect beta-globin RNA metabolism in erythroid tissues. Three thalassemic alleles were studied, each of which harbors either a frameshift or a nonsense mutation. These mutations result in the premature termination of beta-globin mRNA translation and an abnormally low level of beta-globin mRNA in the peripheral blood of thalassemic patients. Comparative studies of mice that express any of the beta zero-thalassemic transgenes with mice that express a normal human beta-globin transgene demonstrated that all three thalassemic mRNAs are metabolized in erythroid tissues abnormally. RNA blotting and S1 nuclease transcript mapping revealed for each thalassemic transgene that (i) the full-length mRNA is abnormally short-lived and (ii) in addition to full-length mRNA, three more stable yet smaller RNAs are present. These smaller RNAs are polyadenylated and lack the mRNA 5' end.