Beta°-Thalassemia/Hb E Association

Abstract

Hemoglobin synthesis in a 34-year-old man of Laotian ancestry with Hb E/β°-thalassemia was studied. Hemoglobin electrophoresis exhibited only Hb F and Hb E. Reticulocytes and bone marrow cells showed no Hb A synthesis. The proportion of Hb F increased (from 14 to 50%) with the density of RBCs fractionated on a discontinuous gradient of Stractan. Reticulocytes were also heterogeneous with regard to their density and their Hb F synthesis: the proportion of Hb F synthesis increased with their density. Fractionation of bone marrow cells by density on a discontinuous gradient of Stractan provided populations of cells at different stages of maturation, the more mature having the greater density. Study of hemoglobin synthesis in bone marrow cells indicated that the proportion of γ-chains synthesized increased and the pool of free α-chains decreased with erythroblast maturation; in contrast, the proportion of βE-chains compared to α-chain synthesis remained constantly low. These results provide evidence that the increased amount of Hb F found in the blood of the patient was mostly due to the positive selection, in bone marrow and in peripheral blood, of cells containing Hb F. In contrast, colonies of early erythroid precursors derived from the blood of the patient exhibited an enormous reactivation of Hb F synthesis in culture. The low proportion of βE-chain synthesis (about 30% of α-chain synthesis) remained unchanged during the erythroid maturation of most immature erythroblasts to reticulocytes. The combination of two thalassemic alleles, one totally deficient (β°) the other partially deficient (βE), can explain the clinical severity of the association β⁰-thalassemia/Hb E.

Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys).

“…The total /3a mRNA ratios observed were 0.28 for patient 1, 0.20 for patient 2, and 0.49 in the patient with Hb E trait (Fig. 6) (9,10), despite mild instability demonstrable in vitro (32,33).…”

“…Double heterozygosity for Hb E and p-thalassemia is frequently associated with a moderately severe ,p-thalassemia syndrome, the molecular basis of which has not been well defined (2)(3)(4)(5). It has been suggested that the thalassemia-like phenotype of Hb E disorders results from impaired synthesis of iE_globin (6)(7)(8)(9)(10), or, perhaps from I3E_globin chain instability (11,12). Either mechanism could result in a limited supply of the abnormal f8-globin chain and lead to decreased net accumulation of Hb E. To define more precisely the pathogenesis of Hb Table I.…”

Hemoglobin Mississippi (beta 44ser----cys). Studies of the thalassemic phenotype in a mixed heterozygote with beta +-thalassemia.

“…Erythrocyte proteases are present in both cell cytoplasm and membrane, and those that are soluble are active at neutral pH and are ATP-dependent enzymes (23, 35,36). They are capable of degrading abnormal proteins (23, 37,38) and are likely to hydrolyze proteins that become redundant (39), such as the free a-and #-chains that appear in the thalassemias (40)(41)(42)(43)(44)(45)(46)(47). These proteases may preferentially attack a-globin chains (46) and denatured globin chains, and play a role in the pathophysiology of the thalassemias and unstable hemoglobins.…”

Hemoglobin Evanston (alpha 14 Trp----Arg). An unstable alpha-chain variant expressed as alpha-thalassemia.

“…6 illustrates the findings from a very short (2 min) synthesis study. In this experiment the incubation was terminated abruptly by lysis ofthe cell suspension in several volumes of ice-cold 2.5 mM E-aminocaproic acid, which was included to retard proteolytic activity (43). Under shown by the arrow.…”