Four base‐pair DNA deletion in human Aγ globin‐gene promoter associated with low Aγ expression in adults

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Abstract
Summary Fetal haemoglobin (α2γ2) is predominant in red cells of the fetus and newborn baby, and is largely replaced after birth by adult haemoglobin (α2β2). The two types of γ chains (Aγ and Gγ) are generally less than 1% of total β-like chain in adults, and the Gγ:Aγ ratio is typically 40:60. Higher Gγ values (> 50% of γ chain) are frequently associated with a T for C nucleotide substitution 158 base pairs 5’of the Gγ Cap site (-158). The first exception to this rule was a β -thalassaemia in a Black family that was associated with about 60%Gγ in heterozygotes. A DNA fragment containing the Gγ and Aγ genes of the high Gγ haplotype of this case has now been cloned. DNA sequencing from - 383 to the Cap site showed no differences from normal for the Gγ gene, except for C at - 158. For the Aγ gene, however, a deletion of four base pairs (AGCA) at - 222 to - 225 was found. It is hypothesized that this deletion causes reduced Aγ 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.
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