| Over 95% of the Hb found in adult humans is HbA, with the α2β2 globin chain composition. HbA2 accounts for 2-3% of the total and has an α2δ2 polypeptide composition. HbA2 is elevated in β-thalassemia, a disease characterized by a deficiency in β-globin biosynthesis. Functionally, these two adult Hbs are indistinguishable. Not surprisingly, mutations of the gene encoding δ-globin are without clinical consequence.
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| Another minor Hb is fetal Hb, HbF; its subunits are α-globin and γ-globin. While it accounts for no more than 1% of adult Hb, HbF predominates in the fetus during the second and third trimesters of gestation and in the neonate. Gene switching on chromosome 11 causes HbF to decrease shortly after birth. The most striking functional difference between HbF and HbA is its decreased sensitivity to 2,3-BPG. Comparison of the primary structures of the β- and γ- polypeptides reveals a replacement of His143 β by serine in γ-globin (Fig. 4.7). Consequently, two of the cationic groups that participate in the binding of the anionic allosteric effector are no longer present. Predictably, the interaction of 2,3-BPG with HbF is weaker, resulting in an increased affinity for O2 (P50 = 19 mm Hg for HbF versus 27 mm Hg for HbA) and a greater stabilization of the oxygenated R-state. The direct benefit of this structural and functional change in the HbF isoform is a more efficient transfer of O2 from maternal HbA to fetal HbF (Fig. 4.3). The HbF variant, barely detectable in most adults, often increases up to 15-20% in individuals with mutant adult Hbs, such as sickle cell disease. This is an example of the body's compensatory response to a pathologic abnormality. Evaluation of many Hb variants is performed by electrophoretic and chromatographic analysis (Fig. 4.8).
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