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

In hereditary persistence of fetal hemoglobin, Hb F (a₂?₂) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high (A)? values. The propositus was a sickle cell patient with ~25% Hb F and 68.4% (A)?. He was heterozygous for the Benin (#19) and Mor ß(s) haplotypes. Five AS relatives with the Mor haplotype had 2.5% ± 0.9% fetal hemoglobin and 92.8% ± 2.8% (A)?, 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)? and (A)? genes of the Mor haplotype was cloned, and the (G)? and (A)? promoters sequenced from -383 to beyond the Cap sites. The Mor (G)? gene was normal, but the (A)? gene had a unique C?T mutation at -202. A different mutation at -202 of (G)? (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)? and (A)? promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.