Alpha-globin mRNA instability in hemoglobin constant spring

As shown in the top panel of this figure, the synthesis of alpha globin mRNA and the levels of alpha-CP stabilizing proteins decline during the mid stages of erythroblast maturation. Because alpha-CP binding enhances stabilization of the Poly (A) 3' tail of mRNA by Poly (A) binding proteins, this leaves globin mRNA more susceptible to ribonuclease degradation in the late erythroblasts and circulating reticulocytes. This is illustrated in sections A and B of the lower panel for mRNA of normal alpha chains, which are stable in bone marrow precursors because of the binding of alpha-CP binding proteins (white oval with diagonal striping), and less stable in reticulocytes because of their absence. In red cell precursors in patients with the thalassemic hemoglobin Constant Spring, which contains a mutated termination codon, alpha-CP binding is blocked by ribosomal "readthrough" through the normally untranslated 3' Poly (A) tail region, which contains the alpha-CP binding sites (section C). This renders alpha chain (Constant Spring) mRNA unstable in early erythroblasts and very unstable in reticulocytes (section D).