Synthesis of Hb Lepore(α₂δ β₂): Influence of δ and β Nucleotide Sequence on Synthesis of δ β Chain

Abstract

MATURE red cells of heterozygotes for Hb Lepore Boston^1,2 contain three haemoglobins in the following proportions: Hb A (α₂β₂) 83–85%; Hb A₂ (α₂δ₂) 1–2%; and Hb Lepore (α₂δβ₂) 14–15%. Hb A and Hb A₂ are normal constituents of erythrocytes but Hb Lepore is an abnormal haemoglobin resulting from an unequal cross-over between the δ and β chain genes during meiosis³. As a result, heterozygotes have one δ chain gene, one β chain gene, and their alleles fused to —δβ—. Because all three haemoglobins are stable, the proportion of each within the cell must represent the different expression of the three non α chain genes (β;δ;δβ) during maturation of the stem cell. The expression of the fused δβ gene is of special interest; because of the cross-over, transcription of its mRNA will be initiated at a site with the nucleotide sequence of the δ chain gene and terminated at a site with that of the β chain gene. The intervening structural gene has 60–80% δ chain gene nucleotide sequence and the remainder is the β chain. The mRNA transcribed must have a similar structural relationship. The problem is to determine at what level the expression of the δβ chain gene is governed by the δ chain nucleotide sequence, and also what influence the nucleotide sequence of the β chain gene has on this expression. These are fundamental questions in the understanding of the control of δ and β chain synthesis, and erythroblasts of heterozygotes for Hb Lepore offer a unique system with which to answer them.