The synthesis of haemoglobin E
Hb E (α2β226 glu→lys) is one of tne most common haemoglobin variants, found in an estimated 30 million people in South-East Asia. Homozygotes for Hb E are only mildly anaemic but compound heterozygotes with β thalassaemia have a severe clinical disorder which is the commonest form of symptomatic thalassaemia in S.E. Asia. The reasons for the high frequency of the S E gene and the severity of its interaction with β thalassaemia have never been adequately explained. We have studied eight Hb E homozygotes and nine heterozygotes all of S.E. Asian origin. In peripheral blood reticulocytes of homozygotes there was marked deficit of βE chain synthesis relative to α chain synthesis (α/βE ratio 2.0-3.3) and this was also observed to a lesser degree in the heterozygotes (1.23-2.19). There was no evidence that this was due to rapid destruction of the newly synthesised βE chains, nor that Hb E was preferentially destroyed during the lifespan of the red cell. Measurement of the ratios of α/β globin mRNA in the reticulocytes of these subjects showed E a deficit of 3 mRNA consistent with the decreased βE chain synthesis in these cells. Assessment of α/β mRNA ratios in bone marrow samples suggested normal transcription of βE mRNA and transport out of the nucleus but that once in the cytoplasm the βE mRNA was relatively unstable. The nature of the mRNA defect is unknown and could result either from the base substitution responsible for the amino acid change or from a second independent mutation in this gene. Thus the βE gene acts as a mild β thalassaemia gene, the defect acting at a pretranslational level. This explains why on interaction with β thalassaemia there is marked deficit of β chain production leading to a disorder of clinical importance.