title: Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia?
abstract: Hemoglobin E (HbE; alpha2beta226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous beta thalassemia. Yet, when it is inherited together with a beta thalassemia allele, the resulting condition, HbE/beta thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the beta thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37 degrees C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/beta thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/beta+ thalassemia red blood cells age. Globin binding to membranes was assessed and only alpha globin chains were found, in contrast to other unstable hemoglobins in which both alpha and beta chains were present. However, in experiments performed on blood from HbE/beta thalassemics in the temperature range 39 degrees C to 41 degrees C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/beta thalassemia is primarily the result of the interaction of two beta thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia.
authors.affiliation: MRC Molecular Haematology Unit, Institute of Molecular Medicine, University of Oxford, The John Radcliffe, Headington, Oxford, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Rees
authors.forename: J B
authors.initials: JB
authors.lastname: Clegg
authors.forename: D J
authors.initials: DJ
authors.lastname: Weatherall
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency; D001831:Body Temperature; D002499:Centrifugation, Density Gradient; D004910:Erythrocyte Membrane / Q000378:metabolism; D005914:Globins / Q000096:biosynthesis; D006446:Hemoglobin E / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D018384:Oxidative Stress; D013997:Time Factors; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics
chemical_list: D005914:Globins; D006446:Hemoglobin E; D015720:5'-Nucleotidase