Fetal hemoglobin synthesis in sickle cell anemia: Some molecular considerations

Abstract

An ability to maintain high levels of fetal hemoglobin (Hb F) has been associated with the amelioration of the clinical severity of the sickle cell disease (SS). Clinical efforts to increase the Hb F level of the patients have, however, yielded variable therapeutic response. In an attempt to further elucidate the underlying molecular basis, in vitro Hb F synthesis was studied in erythroid progenitor (BFU-E) cells obtained from SS patients and their heterozygous (AS) relatives with varying genetic backgrounds. This allows us to study the Hb F biosynthesis pattern uncomplicated by the influence of the preferential survival of "F cells" in vivo. The Hb F levels and the relative concentrations of its constituent gamma globin chains, G gamma and A gamma, were assayed using the reversed phase HPLC method. A percentage increase in the fetal hemoglobin content was observed in the lysates of the erythroid progenitor cells relative to the circulating peripheral blood erythrocyte values in SS patients and their AS relatives with different beta S haplotypes reflecting the intrinsic capacity of fetal hemoglobin synthesis in these subjects. No such increase was observed in the patient with the Mor haplotype. Furthermore, the Hb F synthesized in the BFU-E colonies was more of the adult type, as evidenced by the decrease in the percent G gamma level relative to the corresponding peripheral blood values of the subjects in all the haplotype groups studied. The Mor haplotype was again an exception, synthesizing fetal hemoglobin more of the fetal type.

Changes in the G Gamma- and A Gamma-Globin mRNA Components of Fetal Hemoglobin during Human Development

“…It has been proposed that the presence of an alanine ( A Á) instead of glycine ( G Á) at position 136 of the Á-chain may reduce the flexibility of the Á-chain and interferes with its molecular interaction with the sickle ß-chain. If this is confirmed then A Á would be less effective than G Á in preventing the polymerization of the sickle ß-chain [12]. In this context, it is interesting that both butyrate and hydroxyurea selectively increase G Á expression in in vitro studies [13].…”

Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients

“…The presence of an alanine ( A γ) instead of a glycine ( G γ) at position 136 of the γ chain interferes with the interaction between γ chain and sickle ß chain due to a reduced flexibility of A γ. Thus, A γ is less effective than G γ in preventing the polymerization of the sickle ß chain (20).…”