Translational control of hemoglobin synthesis in thalassemic bone marrow

Previous studies of beta-thalassemic reticulocytes have implied a decreased amount of functional beta-mRNA but unimpaired translation of the beta-mRNA present. However, the beta/alpha synthetic ratios in beta-thalassemic marrow are higher than those observed in reticulocytes of the same patients. This could imply that marrow cells contain an abnormally functioning beta-mRNA no longer active in reticulocytes. To test the function of mRNA found in marrow, intact cells were incubated with [(35)S]methionine and the relative amounts of nascent alpha- and beta-chains on polysomes of different sizes were measured by tryptic digestion and determination of the specific activities of the respective peptides. Results showed that in normal and beta-thalassemic marrow, as well as in reticulocytes, beta-chain production, though deficient, occurs predominantly on larger polysomes than the production of alpha-chains. In one patient with severe thalassemia and very little production of beta-chains in marrow or reticulocytes, delta-chain synthesis was found predominantly on larger polysomes than alpha-chain synthesis. These results indicate that in beta-thalassemic as well as in nonthalassemic marrow and reticulocytes, each beta- and delta-mRNA initiates protein synthesis at a rate faster than does each alpha-mRNA, and suggest that the beta-mRNA in contact with polyribosomes is normally functioning but quantitatively deficient in beta-thalassemic marrow as well as in reticulocytes. No translational defect was detected in a similar study performed in reticulocytes of a patient with hemoglobin H disease, suggesting a normally functioning mRNA in contact with polyribosomes in this condition as well. In both thalassemias, unbalanced synthesis of alpha- and beta-chains was more pronounced on polysomes than in completed chains. This difference possibly reflects a compensatory delay in translation of the nonthalassemic chain, which is present in excess.