Variability in the interaction of β-thalassemia with the α-chain variants Hb G-Philadelphia and Hb Rampa

Abstract

Two unrelated families are reported in which a β-thalassemia trait occurred with a heterozygosity for Hb G-Philadelphia (α2 68(E17)Asn → Lys β2) in one family and with Hb Rampa (α2 95(G2)Pro → Serβ2) in the other. The percentage of Hb G-Philadelphia was not influenced by the simultaneous presence of a β-thalassemia determinant, but that of Hb Rampa was decreased from 20% in the simple heterozygote to about 6% in persons with the Hb Rampa-β-thalassemia combination. Data from in vitro recombination experiments with isolated αX, αA, and βA chains, with heme attached, indicated a preferential formation of Hb A over Hb Rampa but not over Hb G-Philadelphia in conditions of relative β-chain deficiency. This suggests that the rate of assembly of monomers to form dimers or tetramers can be an important mechanism of controlling the quantity of certain hemoglobin variants with critical substitutions in heterozygotes.