The results show that high HbF production in SEA-HPFH occurs from a deletion of the 3'HS1 sequence and the juxtaposition of the HPFH-3 enhancer downstream to the delta-globin gene.
The compound heterozygote is a healthy man with 43% HbF, Ggamma/Agamma ratio (27:73) differing from that of 10 simple heterozygotes for the Greek HPFH (92:8), normal levels of total Hb (13.3 g/dl), and reduced HbA2 levels comparing with the levels of beta-thal heterozygotes for the same mutation.
We have tested this hypothesis for an element that covers the minimal distance between the thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-thalassemia, located 5' of the delta-globin gene.
The Spanish type of delta beta-thalassemia is a mild thalassemic condition due to a large deletion starting at the Alu I repeat between the A gamma and delta-globin genes immediately 3' to the RIH probe and extending 11 and 17 kb downstream of the 3' endpoints of HPFH 1 and HPFH 2, respectively.
The pattern of inheritance of several polymorphic restriction sites associated with the beta-gene cluster, and spanning a region of 52kb, demonstrates that a determinant for hereditary persistence of fetal hemoglobin (HPFH) segregates independently from the non-alpha globin gene cluster, as we postulated several years ago on purely genetical grounds.
In all four previously described HPFH, a repetitive Alu I region 5' to the delta globin gene is largely or completely deleted; the 5' end of the new HPFH is consistent with this common feature.
Fragments of the non-alpha-globin cluster from two patients were cloned in cosmid and phage lambda vectors, and assigned to either the HPFH or beta-thalassemic chromosome on the basis of the demonstration of a polymorphic BglII site in the HPFH gamma-globin cluster.
The possible linkage between a gene causing heterocellular hereditary persistence of fetal hemoglobin (HPFH) and human non-alpha globin loci has been studied in a large Sardinian family.
Correlation of haematological data and the location of deletions in two cases of HPFH and one case of deltabeta-thalassaemia suggest that a region of DNA located near the 5'-end of the delta-globin gene may be involved in the suppression in cis of gamma-globin gene expression in adults.