Increased expression of the (G)γ and (A)γ globin genes associated with a mutation in the (A)γ enhancer

G. Balta, H. E. Brickner, S. Takegawa, H. H. Kazazian, T. Papayannopoulou, B. G. Forget, G. F. Atweh

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


We have previously described a unique type of δβ-thalassemia in a Chinese family characterized by increased expression of the (G)γ and (A)γ fetal globin genes in the absence of a large deletion in the β-globin gene cluster. Our earlier study of the β-globin gene on this δβ-thalassemia chromosome showed a promoter mutation in the TATA box. In this report, we describe the results of our study of the fetal globin domain of this δβ- thalassemia chromosome. We have cloned a 13-kb DNA fragment that includes the (G)γ and the (A)γ genes and the 3' (A)γ enhancer element of this δβ- thalassemia chromosome. DNA sequence analysis of the (G)γ and (A)γ-globin genes including their promoters did not show any mutations, but analysis of the putative enhancer element downstream from the (A)γ-globin gene showed a C to T substitution 2,401 nucleotides downstream from the (A)γ cap site. We performed DNA linkage analysis to determine if this mutation is unique to this chromosome or represents a common polymorphism. Our linkage analysis showed that this mutation is not a common polymorphism and that it is also not an intrinsic part of the haplotype of the chromosome on which it was found. We also studied the interaction of nuclear proteins from erythroid and nonerythroid cells with the DNA sequences surrounding this mutation. We have shown by in vitro DNase I footprinting that this mutation falls within a region that is occupied by a novel DNA-binding protein that binds to this site in nuclear extracts from erythroid, but not nonerythroid cells. The binding of this nuclear protein to DNA appears to be dependent on GATA-1 binding to an adjacent GATA-1 site. We have also developed a new functional assay to compare the activity of the normal and mutant (A)γ enhancer elements in erythroid cells. Analysis of the activity of the mutant enhancer shows that the mutation completely eliminates all enhancer activity in this assay. These findings suggest that this mutation of the (A)γ enhancer on a chromosome that carries a partially inactivated β-globin gene may be responsible for the increased expression of both γ-globin genes seen in this condition.

Original languageEnglish (US)
Pages (from-to)3727-3737
Number of pages11
Issue number12
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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