Defective synthesis of HbE is due to reduced levels of βE mRNA

Abstract

Hb E (.alpha.2.beta.226Glu .fwdarw. Lys) is one of the commonest Hb variants. There are an estimated 30 million human carriers of the .beta.E gene in Southeast Asia, where they comprise more than 50% of the population in some areas; the reasons for this high frequency were never adequately explained. Homozygotes for HbE may be mildly anemic, but they do not have any clinical disability. Individuals heterozygous for both .beta.E and .beta. thalassemia (HbE/.beta. thalassemia) have a severe clinical disorder which in some cases may approach that seen in homozygous .beta. thalassaemia and which is by far the commonest form of symptomatic thalassemia in the Indian subcontinent and southeast Asia. HbE is the only common structural variant which interacts with .beta. thalassemia to produce such a severe disorder and the underlying mechanism of the interaction is not known. Several homozygotes and heterozygotes for HbE were studied. The .beta.E chain is inefficiently synthesized and produces the phenotype of a mild form of .beta. thalassemia; when inherited together with .beta. thalassemia it causes a marked .beta.-chain deficit. The mechanism for the defective production of .beta.E chains seems to be a reduction of .BETA.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 .beta. globin gene.