The -158 (C-->T) promoter mutation is responsible for the increased
transcription of the 3' gamma gene in the Atlanta type of hereditary
persistence of fetal hemoglobin
DG Efremov, AJ Dimovski and TH Huisman
Department of Biochemistry and Molecular Biology, Medical College of
Georgia, Augusta 30912-2100.
The Atlanta type of hereditary persistence of fetal hemoglobin (HPFH) is
characterized by a mild elevation of Hb F (2% to 5% in heterozygotes),
almost exclusively of the G gamma type (more than 90%). Gene-mapping
analysis has identified this condition as a -G gamma-G gamma- arrangement
with the -158 (C-->T) substitution in the promoters of both G gamma
genes. We have reevaluated this condition in members of two families.
Sequence analysis identified only two changes in the 3' gamma gene as
compared with the A gamma gene from a chromosome with haplotype no. 3 (or
Senegal), namely the -158 (C-->T) promoter mutation and the C-->G
change in codon (CD) 136, which accounts for the -G gamma- G gamma-
phenotype. The absence of any other nucleotide (nt) substitution provides
genetic evidence that the -158 (C-->T) change is primarily responsible
for the elevated Hb F levels associated with this condition. A quantitative
reverse transcription/polymerase chain reaction (RT/PCR) procedure,
presented in detail in this report, was developed to determine the effect
of this mutation on the transcription of individual gamma genes in four
individuals with the Atlanta type of HPFH. Both gamma-globin genes, ie, the
(5') G gamma and the (3') G gamma-Atlanta genes of the Atlanta type of HPFH
chromosome, expressed elevated amounts of transcripts, which were present
in nearly equal amounts. This shows that the -158 (C-->T) mutation
exerts its effect on the transcriptional rate of the gene with which it is
associated.
Volume 83,
Issue 11,
pp. 3350-3355,
06/01/1994
Copyright © 1994 by The American Society of Hematology
