Erythroblastic Inclusions in Dominantly Inherited β Thalassemias

Abstract

AbstractWhile the precipitation of unstable variant β-globin chains has been implicated as a major pathogenic mechanism in dominantly inherited β thalassemia, their instability and presence in intra-erythroblastic inclusions have not been conclusively shown. We report the investigation of two cases of dominantly inherited β thalassemia due to heterozygosity for the β-codon 121 G-T mutation. In one case, we were able to demonstrate the presence of an abnormal β-globin chain in both peripheral blood reticulocytes and bone marrow erythroblasts, and to assess its stability in relation to the substantial amounts of mutant β 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 α-globin chains, but also β chains. The data confirm previous suggestions that the cellular pathology underlying this group of β thalassemias is related to the synthesis of highly unstable β-globin chain variants, which fail to form functional tetramers and precipitate intracellularly with the concomitant excess α chains, leading to increased ineffective erythropoiesis.