Defective synthesis of HbE is due to reduced levels of β^E mRNA

Abstract

Haemoglobin E (α₂β₂^26GlU→Lys) is one of the commonest haemoglobin variants. There are an estimated 30 million carriers of the β^E gene in South-East Asia, where they comprise more than 50% of the population in some areas^1,2; however, the reasons for this high frequency have never been adequately explained. Homozygotes for HbE may be mildly anaemic, but they do not have any clinical disability^3,4. However, individuals heterozygous for both β^E and β thalassaemia (HbE/β thalassaemia) have a severe clinical disorder which in some cases may approach that seen in homozygous β thalassaemia^3,5,6 and which is by far the commonest form of symptomatic thalassaemia in the Indian subcontinent and South-East Asia. Haemoglobin E is the only common structural variant which interacts with β thalassaemia to produce such a severe disorder and the underlying mechanism of the interaction is not known. We have studied several homozygotes and heterozygotes for HbE and show here that the β^E chain is inefficiently synthesized and produces the phenotype of a mild form of β thalassaemia; hence, when inherited together with β thalassaemia it causes a marked β-chain deficit. Furthermore, the mechanism for the defective production of β^E chains seems to be a reduction of β^E mRNA, a most unexpected finding in a disorder caused by a single amino acid substitution and presumably by a single nucleotide change in the DNA of the β globin gene.