Fig. 1

a Arrangement of the β- and α-globin gene clusters and their regulatory regions, The LCR (locus control region) and HS-40 are the major enhancers of expression within the HBB and HBA gene clusters, respectively. HbA is a tetramer of normal α- and β-globin chains. b. The expression of the globin genes changes throughout development. Embryonic ε globin is produced in the embryo, fetal γ-globin during most of gestation and the major adult β globin from mid-gestation onwards. Not shown are the α-globin-like ζ globin genes and the α-globin genes whose expression starts early in embryogenesis. c. Classification of hemoglobinopathies and thalassemia. Hemoglobinopathies result from mutations that change the primary structure of globin. The most common examples are HbS (HBB glu6val), HbC (HBB glu6lys), and HbE (HBB glu26lys). Rare structural variants affect the oxygen delivery functions of the molecule, its stability and its resistance to oxidation. Thalassemia is caused by mutations that affect transcription and translation of any globin gene by nearly all possible mechanisms. They lead to decreased or absent production of a globin subunit; α and β thalassemia are most common. In all thalassemias the phenotype is a consequence of imbalanced synthesis of globin subunits allowing globin unincorporated into a tetramer to precipitate and otherwise damage the erythrocyte. About 1600 structural variants and thalassemia mutations have been cataloged in The Hemoglobin Variant Database [1]. All thalassemias and hemoglobinopathies can interact in various ways and many different compound heterozygous conditions occur. (Adapted from [51])