The biologic implications of a rare hemoglobin mutant that decreases oxygen affinity

Abstract

Blood from seven newborns, a 13-y-old, and seven adult family members with a suspected hemoglobinopathy because of unexplained cyanosis was obtained for analysis to determine Hb oxygen affinity and to characterize and quantify the Hb variants. Their oxygen saturation was 76 to 84%. The P50 was 30.3 ± 2.9 for the newborns and 32.5 ± 2.6 mm Hg for their related adults. In the same order, the plasma erythropoietin was 7.4 ± 2.9 and 15.9 ± 3.7 mU/mL, whereas 2,3-diphoshoglycerate was 16.1. ± 2.9 and 15.9 ± 3.7 μmol/g Hb. In four of the newborns with increased P50, the mother had a normal P50 (27 mm Hg), which indicated a greater maternal oxygen affinity than the fetus with no adverse effects on the fetus. Genetic analysis of α-globin genes demonstrated a heterozygous mutation on the α2 gene [α94(G1)Asp→His] for each of the newborns and their related adults. The same mutation was found on the α1 gene in an adolescent and her father. The mRNA measurements showed that the α2- to α1-globin mRNA mean ratio was 2.5, α2 mutant globin mRNA/total α2-globin mRNA was 45.0%, whereas the α1 mutant globin mRNA/total α1-globin mRNA was 37.8%. The level of α2 mutant globin/total α-globin was 27.3 ± 1%, and α1 mutant globin/total α-globin was 23.8 ± 1%. The percentage of synthesized α2 and α1 mutant globins was 27.5 ± 2 and 26.1 ± 1, respectively. The ratio of the α2/α1 mutant globins was 1.1, which corresponded to a ratio at the mRNA level of α2/α1 of 2.5 ± 0.5, which suggested that there is a less efficient translation of the α2 mRNA than α1 mRNA. The reversal of the physiologic fetomaternal oxygen affinity had no effects on fetal development.