Post-translational control of human hemoglobin synthesis: the role of the differential affinity between globin chains in the control of mutated globin gene expression.

The interactions between beta-thalassemia and the human hemoglobin (Hb) alpha-chain variants, Hb Hasharon, Hb O Idonesia and Hb J Paris, and between alpha-thalassemia and the beta-chain variants, Hb S, Hb C and Hb G San José, which are characterized by preferential decrease of the abnormal Hb level in peripheral bloods, have been studied. Both biosynthesis studies in reticulocytes and determination of the relative affinity of abnormal chains for normal complementary chains by in vivo recombination experiments, involving globin chains previously isolated in their native form, have been carried out in order to provide insights on the molecular events following the synthesis of the mutant chains under conditions of complementary chain deficiency. Furthermore, we have measured the relative affinity for complementary chain of beta D Los Angeles- and alpha J Rovigo-chains, the level of which does not decay in thalassemic carriers, and of alpha Legnano- and beta Osu Christiansborg-chains, which have not yet been observed in association with thalassemias. Our experiments indicated that the differential affinity for beta-chains is not always the major post-translational control mechanism which regulates the level of certain alpha-chain variants in beta-thalassemic heterozygotes, and that preferential removal of abnormal chains by proteolytic enzymes is likely to play an important role in most cases. On the other hand, the low affinity of certain variant beta-chains for alpha-chains may offer an explanation for the low level of certain beta-chain variants in peripheral blood of non-thalassemic carriers, as well as to their decrease under conditions of relative alpha-chain deficiency (alpha-thalassemias).