The -158 (C → T) promoter mutation is responsible for the increased transcription of the 3′ γ gene in the Atlanta type of hereditary persistence of fetal hemoglobin

Abstract

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 Gγ type (more than 90%). Gene-mapping analysis has identified this condition as a -Gγ-Gγ- arrangement with the -158 (C → T) substitution in the promoters of both Gγ genes. We have reevaluated this condition in members of two families. Sequence analysis identified only two changes in the 3′γ gene as compared with the Aγ 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 -Gγ-Gγ- 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 γ genes in four individuals with the Atlanta type of HPFH. Both γ-globin genes, ie, the (5′) Gγ and the (3′) Gγ-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. © 1994 by The American Society of Hematology.