As many as 14 different nucleotide changes have been observed in the promoter sequences of the Ggamma- and Agamma-globin genes; five nucleotide changes and one frameshift for Ggamma, and seven nucleotide changes and one 13 bp deletion for Agamma. All 14 are reviewed individually on pages 189 through 198. A short list of all these alleles is presented in Table XVII, together with the total Hb F values in heterozygotes. Mutations in the Ggamma promoter result in a (greatly) increased synthesis of primarily Ggamma chains and those in the Agamma promoter in an increase in Agamma chain synthesis. The values vary greatly for the different Ggamma and Agamma mutations but also for (nearly) identical mutations in the Ggamma and Agamma promoters [for instance, the -202 (C->G and C->T) mutations; the -175 (T->C) mutation; the -114 (C->G and C->T) mutations]. Although the Hb F level appears to be lower in heterozygotes for Agamma mutations than in those for Ggamma mutations, the -175 (T->C) mutations are an exception. Individual data for heterozygotes (with and without Hb S, Hb C, or beta-thal in trans) and a few homozygotes are listed in Fig. 10.
When a Hb abnormality or a beta-thal is present on the opposite chromosome, the Hb F level tends to be significantly higher. Homozygotes have been reported for the -200 (+C; Ggamma) frameshift (48-49%), the -198 (T->C; Agamma) mutation (19.4-20.4%), and the -117 (G->A; Agamma) mutation (24.0-24.0%). Fig. 10 illustrates the considerable variability in Hb F levels which might in part be due to the methodology. This is particularly evident from the data for the -198 (T->C, Agamma) heterozygotes from British and Australian families; no such striking difference was present for the Hb F values observed in Greek and Italian heterozygotes and in Black heterozygotes for the -117 (G->A; Agamma) mutation.
FIG. 10. The quantities of Hb F in numerous carriers of mutations in the promoter regions of the Ggamma- and Agamma-globin genes. All percentages are from publications quoted on pages 189 through 198; data obtained by alkali denaturation are given most frequently; however, percentages obtained by chromatography are listed when FAD values are not available.
Fig. 11 provides the nucleotide sequences of the Ggamma and Agamma promoter segments; these differ only at position +25. Ottolenghi et al (1) discusses in detail the specific locations of the mutations in these segments which are DNA binding sites for ubiquitous and/or erythroid specific proteins. Any nucleotide replacement within these segments likely decreases the binding of these factors, thus affecting the activity of the Ggamma- or Agamma-globin genes. Presumably, the type of nucleotide replacement also influences the level of Hb F in heterozygotes. When a nucleotide change is located adjacent to one of the motifs [for instance, the -110 (A->C; Ggamma) mutation], the effect on the activity of the gene appears to be minimal.
FIG. 11. Mutations in the promoter regions of the Ggamma- and Agamma-globin genes resulting in nondeletional types of HPFH. Section I is a GC rich area which is an Sp-I binding site; section II is an NFE-I binding motif; section III is also a binding site for transcriptional factors. The sequences of the Ggamma and Agamma genes differ only at position +25 (A in Agamma; G in Ggamma). The mutations in the Agamma promoter are listed above, and those in the Ggamma promoter below the sequences.
|1.||Ottolenghi, S., Mantovani, R., Nicolis, S., Ronchi, A., and Giglioni, B.: Hemoglobin, 13:523, 1989.|