Observations on the levels of Hb A₂ in patients with different β-thalassemia mutations and a δ chain variant

Hb A₂ and its variant B₂ (α₂δ₂ 16(A13)Gly→Arg) were quantitated in the blood of subjects with three different types of β-thalassemia and with the δ-B₂ anomaly in cis or in trans to the β-thalassemia determinant. In one family, the δ-B₂ mutation was in cis to a newly discovered codon 47 (+A) frameshift. The levels of Hbs A₂ and B₂ were nearly the same and approximately 70% higher than those in simple Hb B₂ heterozygotes. In two additional families, the δ-B₂ variant was in trans to either a deletion β-thalassemia (1,393 bp) involving part of the β-globin gene and part of the β-globin gene promoter, or to the - 88 C→T promoter mutation. In both instances, the Hb B₂ level was increased by approximately 80%, but the Hb A₂ level was increased by approximately 270% and 200%, respectively. These data indicate two mechanisms that will cause an increase in δ chain production. One is consistent with a general mechanism concerning the relative excess of α chains in β chain deficiencies which will combine with δ chains to form variable levels of Hb A₂ dependent on the severity of the β chain deficiency. The second concerns the loss of β-globin gene promoter activity, perhaps by an absence of (or decreased) binding of specific protein(s) to this segment of DNA and a concomitant increase in δ-globin gene promoter activity in cis.