The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster.

The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3' to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3' breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta)(0) thalassemia) is nearly identical in size and location to that of HPFH-1, but extends an additional 8.5 to 9 kb in the 3' direction, and therefore results in loss of the sequences near the 3' breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.