The Greek A gamma beta+-HPFH observed in a large black family

Several members of a Black family with a heterozygosity for an A gamma beta+-HPFH, shown in 1969 to have relatively low levels of Hb F and a low glycine to alanine ratio in the gamma chain of this Hb F, were reinvestigated. Thirteen of 30 available family members in two generations had the heterozygous form of this condition, which was characterized by a decreased level of Hb A2, an average Hb FAD value of 13.3%, an equal distribution of Hb F over the red cells, and normal hematological values. The gamma chain composition of isolated Hb F was determined by reversed phase high performance liquid chromatography for all 13 heterozygotes and showed an average A gamma value of 84.5%. Hybridization with synthetic oligonucleotides, specific for normal and mutant sequences at positions 111-129 5' to the A gamma globin gene, identified a G----A base substitution at position 117, similar to that seen in subjects with the Greek A gamma-HPFH. Our data support conclusions by others that this replacement is causative of the increased A gamma chain synthesis in this condition. Haplotype analysis supported the suggestion that the G----A substitution occurred as an independent event in this Black family.