Four base-pair DNA deletion in human A gamma globin-gene promoter associated with low A gamma expression in adults

Fetal haemoglobin (alpha 2 gamma 2) is predominant in red cells of the fetus and newborn baby, and is largely replaced after birth by adult haemoglobin (alpha 2 beta 2). The two types of gamma chains (A gamma and G gamma) are generally less than 1% of total beta-like chain in adults, and the G gamma: A gamma ratio is typically 40:60. Higher G gamma values (greater than 50% of gamma chain) are frequently associated with a T for C nucleotide substitution 158 base pairs 5' of the G gamma Cap site (-158). The first exception to this rule was a beta o-thalassaemia in a Black family that was associated with about 60% G gamma in heterozygotes. A DNA fragment containing the G gamma and A gamma genes of the high G gamma haplotype of this case has now been cloned. DNA sequencing from -383 to the Cap site showed no differences from normal for the G gamma gene, except for C at -158. For the A gamma gene, however, a deletion of four base pairs (AGCA) at -222 to -225 was found. It is hypothesized that this deletion causes reduced A gamma globin gene expression in adults, which suggests that promoter elements important for the regulation of fetal haemoglobin expression in adults extend upstream at least to -225.