Erythroblastic inclusions in dominantly inherited beta thalassemias

While the precipitation of unstable variant beta-globin chains has been implicated as a major pathogenic mechanism in dominantly inherited beta thalassemia, their instability and presence in intra-erythroblastic inclusions have not been conclusively shown. We report the investigation of two cases of dominantly inherited beta thalassemia due to heterozygosity for the beta-codon 121 G-T mutation. In one case, we were able to demonstrate the presence of an abnormal beta-globin chain in both peripheral blood reticulocytes and bone marrow erythroblasts, and to assess its stability in relation to the substantial amounts of mutant beta mRNA transcript. The serum transferrin receptor (TfR) level was markedly increased, an indication of increased erythropoietic activity. In both cases, we could show by immunoelectron microscopy that the intra-erythroblastic inclusion bodies, a prominent feature of diseases in this category, contained not only precipitated alpha-globin chains, but also beta chains. The data confirm previous suggestions that the cellular pathology underlying this group of beta thalassemias is related to the synthesis of highly unstable beta-globin chain variants, which fail to form functional tetramers and precipitate intracellularly with the concomitant excess alpha chains, leading to increased ineffective erythropoiesis.