Hemoglobin evanston (α14 trp → Arg). An unstable α-chain variant expressed as α-thalassemia

Abstract

A new hematologic syndrome with phenotypic features of mild Hb H disease was identified in three children from two unrelated black American families. Erythrocytes from each of these children contained Hb H (β4) and Hb Barts (γ4), as well as a slowly migrating hemoglobin fraction that made up 7-10% of the total hemoglobin. The parents of the affected children all showed mild thalassemia-like changes, with one of the parents in each family also expressing the variant hemoglobin; in the latter individuals the mutant α-chains made up <2% of the total, and were present mainly or exclusively in combination with δ-chains in the form of a slowly migrating Hb A2. Purified Hb Evanston showed an increased oxygen affinity, but its Bohr effect, cooperativity, and 2,3-diphosphoglycerate effect were normal. The mutant hemoglobin appeared to have normal stability to heat and to isopropanol, and the stability of its α-chain in an extended time course synthesis study also appeared to be similar to that of α(A). However, the results from short-term globin synthesis studies, and from mRNA translation in vitro, suggest that the two types of α-chains were synthesized at relatively equal rates, with a major fraction of the newly synthesized variant α-chains undergoing rapid catabolism. The hematologic data taken in combination with DNA hybridization and globin synthesis findings indicate that the proposita in each of these families has the genotype -,α(A)/-,α(Ev). These observations suggest that two separate mechanisms are contributing to the α-thalassemia-like expression of Hb Evanston: (a) the newly synthesized α(EV)-chains are unstable and are subject to early proteolytic destruction; and (b) the mutant α-allele is linked to an α-globin gene deletion.