Upstream promoter mutation associated with a modest elevation of fetal hemoglobin expression in human adults.
In hereditary persistence of fetal hemoglobin, Hb F (alpha 2 gamma 2) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high A gamma values. The propositus was a sickle cell patient with approximately 25% Hb F and 68.4% A gamma. He was heterozygous for the Benin (#19) and Mor beta S haplotypes. Five AS relatives with the Mor haplotype had 2.5% +/- 0.9% fetal hemoglobin and 92.8% +/- 2.8% A gamma, 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) Bg/II fragment containing the G gamma and A gamma genes of the Mor haplotype was cloned, and the G gamma and A gamma promoters sequenced from -383 to beyond the Cap sites. The Mor G gamma gene was normal, but the A gamma gene had a unique C----T mutation at -202. A different mutation at -202 of G gamma (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 gamma and A gamma promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.
Gilman
J G
JG
Department of Cell and Molecular Biology, Medical College of Georgia, Augusta 30912.
Mishima
N
N
Wen
X J
XJ
Kutlar
F
F
Huisman
T H
TH
D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics; D001483:Base Sequence; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000302:isolation & purification; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic
D005319:Fetal Hemoglobin