Expression of G_γ and A_γ Globin Genes in Human Adults

Abstract

Expression of the human fetal G_γ and A_γ globin genes declines shortly after birth, and adults generally have less than 1% fetal hemoglobin or Hb F (α₂γ₂). However, some adults with hereditary persistence of fetal hemoglobin (HPFH) have elevated expression of either the G_γ or A_γ gene due to a mutation in its upstream promoter. Mutations with strong efects on expression have been found at -175 and -202 of the G_γ gene and at -117, -196 -198 and -202 of the A_γ gene. Mutations at -158 and -161 of G_γ have weaker effects, which are observable primarily as increases in the G_γ:A_γ ratio. Published data are reviewed which suggest that the -158 mutation may lead to observable elevations of Hb F in SS and βd`-thal patients and occasionally in normal non-anemic individuals. These data also suggest that additional high Hb F determinants are linked to Benin, Bantu and Asian β^S haplotypes in some instances. A model based on data from SV40 is presented which suggests that specific DNA sequence motifs of the γ globin gene may bind regulatory proteins. It is proposed that the -158 and -161 mutations have weak effects because they are located on the fringe of regulatory sequence motifs.