Heterogeneity in the molecular basis of hereditary persistence of fetal haemoglobin

Abstract

In hereditary persistence of fetal haemoglobin (HPFH), there is a uniformly high level of synthesis of fetal haemoglobin (Hb F: α₂γ₂) in all red cells of affected adults. Other hereditary disorders of human haemoglobin synthesis may also be associated with persistent synthesis of Hb F into adult life, but usually at a lower level and in only a selected population of red cells. Previous studies in the common type of HPFH that occurs in blacks have demonstrated the presence of a total deletion of the linked β- and δ-globin genes of the adult haemoglobins Hb A (α₂β₂) and Hb A₂ (α₂δ₂)^1–3, including approximately 4 kilo-bases of the DNA flanking the 5′ end of the δ gene. In contrast, δβ-thalassaemia, in which Hb F synthesis is not as elevated or uniform as in HPFH, is associated with a partial deletion of the δ gene that leaves intact the 5′-flanking DNA of the gene^1–5. These results provided support for previous theories⁶ that regulatory sequences involved in the suppression of γ-globin gene expression might be located between the γ- and δ-globin genes, and that deletion of these sequences might be responsible for the continued expression of γ-globin genes in HPFH. To extend these observations, gene mapping studies of the non-α-globin genes have now been carried out in two additional individuals wth HPFH using restriction endonuclease digestion and gel blotting of total cellular DNA according to the method of Southern¹⁶. The results indicate that the molecular defects associated with HPFH are heterogeneous even in cases with similar phenotypes such as in the common variety of HPFH that occurs in blacks.