Upstream promoter mutation associated with a modest elevation of fetal hemoglobin expression in human adults

Abstract

In hereditary persistence of fetal hemoglobin, Hb F (α2γ2) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high (A)γ values. The propositus was a sickle cell patient with ~25% Hb F and 68.4% (A)γ. He was heterozygous for the Benin (#19) and Mor β(s) haplotypes. Five AS relatives with the Mor haplotype had 2.5% ± 0.9% fetal hemoglobin and 92.8% ± 2.8% (A)γ, whereas two with the Benin haplotype had normal fetal hemoglobin (0.5%). The Mor haplotype is thus associated with the elevated Hb F in this family. The 13-kilobase (kb) BglII fragment containing the (G)γ and (A)γ genes of the Mor haplotype was cloned, and the (G)γ and (A)γ promoters sequenced from -383 to beyond the Cap sites. The Mor (G)γ gene was normal, but the (A)γ gene had a unique C→T mutation at -202. A different mutation at -202 of (G)γ (C→G) was previously detected by other researchers in association with considerably higher Hb F in AS cases (15% to 25%). These data suggest either that -202 mutations affect the (G)γ and (A)γ promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.