β-Thalassemia Intermedia with Exceptionally High Hemoglobin A2: Relationship to Mutations in the β-Gene Promoter

Small deletions of the 5′ portion of the β-globin gene that remove the promoters but stop 3′ to the δ-globin gene are recognized as the sole cause of β-thalassemia with exceptionally high hemoglobin A2 (HbA2) levels. Two patients with β-thalassemia intermedia and exceptionally high levels of HbA2 (10.4 and 12.0%) were examined. One patient was a combined heterozygote for the −88 C→T and a novel −87 C→A mutation, while the other was homozygous for the −29 A→G β+-thalassemia mutation. The remainder of the β genes were normal. There was no evidence for deletions involving the 5′ portion of the β gene or the region between the β and δ genes. Gene mapping studies excluded the possibility of a βδ-anti-Lepore hemoglobin gene with β promoters and δ coding sequences. There were no mutations in the promoters of the Gγ or Aγ- globin genes that have been associated with the hereditary persistence of HbF phenotype. The δ-globin gene promoters were normal from codon 17 to position −145 relative to the mRNA capping site. There appears to be considerable heterogeneity of HbA2 and HbF levels in patients who are homozygous or mixed heterozygotes for mutations in the TATA box and other promoter elements of the β-globin gene. The capacity for proteolysis within the erythrocyte may vary among individuals. The authors hypothesize that in the exceptionally high HbA2β-thalassemia intermedia phenotype, proteolysis of superfluous α-globin chains is less efficient than in patients with customary levels of HbA2. The relative surfeit of α-chains may combine with δ-globin and account for the unusually high HbA2 levels.