The Effect of α-Thalassemia on the Level of Hybrid Hemoglobin Variants in Heterozygotes

Abstract

The influence of a relative deficiency in alpha chain production on the amount of Hemoglobins Kenya, P-Nilotic, and Lepore was determined. The level of these hybrid hemoglobins in heterozygotes was correlated to various states of alpha chain deficiency by: 1) quantitation of the variants in blood samples and comparing these data with the number of alpha globin genes determined by gene mapping, 2) in vitro recombination experiments involving isolated non-alpha chains and normal alpha chains, and 3) in vitro heat stability analyses of the isolated hemoglobins. Hb Kenya, composed of normal alpha and gamma-beta hybrid chains, is heat labile, has a decreased ability to combine with alpha chains, and its level in heterozygotes is greatly decreased when a concomitant alpha-chain deficiency (alpha-thalassemia) is present. Such a posttranslational control mechanism was not observed for Hb Lepore, with normal alpha chains and delta-beta hybrid chains, and Hb P-Nilotic, with normal alpha chains and beta-delta hybrid chains. The latter two variants are heat stable, and their hybrid chains combine equally well as normal beta chains with normal alpha chains. Hb P-Nilotic is more heat stable than Hb A and its in vitro formation is increased over that of Hb S, and perhaps even Hb A, in conditions of severe alpha chain deficiency.