Abstract

In hereditary persistence of fetal haemoglobin (HPFH), there is a uniformly high level of synthesis of fetal haemoglobin (Hb F: ₂₂) 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 - and -globin genes of the adult haemoglobins Hb A (₂₂) and Hb A₂ (₂₂)^1–3, including approximately 4 kilo-bases of the DNA flanking the 5' end of the gene. In contrast, -thalassaemia, in which Hb F synthesis is not as elevated or uniform as in HPFH, is associated with a partial deletion of the 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 -globin gene expression might be located between the - and -globin genes, and that deletion of these sequences might be responsible for the continued expression of -globin genes in HPFH. To extend these observations, gene mapping studies of the non--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.