A naturally occurring gamma globin gene mutation enhances SP1 binding activity.
Transcription of the human fetal globin genes in erythroid cells is tightly regulated during different stages of development and differentiation. Two naturally occurring mutations 202 base pairs upstream of the duplicated gamma globin genes are associated with incorrectly regulated gamma globin gene gene expression; elevated levels of fetal globin are synthesized during adult life. A C-to-G base substitution upstream of the G gamma-globin gene is highly correlated with a dramatic increase in gene expression. It increases the similarity of the region to the consensus Sp1 recognition site. We determined that the mutated DNA had a 5- to 10-fold-higher affinity for Sp1 than did normal gamma globin gene sequence. We also observed a reduction in normal factor-binding activity. A different substitution at -202, C to T, upstream of the A gamma-globin gene was associated with a more moderate increase in fetal globin expression. This mutation decreased the similarity of the sequence to an Sp1 recognition site. We determined that it did not result in enhanced Sp1 binding but did alter normal factor binding. We suggest that these changes in nuclear protein-binding properties detected in vitro are responsible for the enhanced gamma globin gene expression found in -202 G gamma beta + patients with hereditary persistence of fetal hemoglobin.
Duke Scholars
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- Transcription, Genetic
- Transcription Factors
- Sp1 Transcription Factor
- Simian virus 40
- Regulatory Sequences, Nucleic Acid
- Oligonucleotide Probes
- Mutation
- Molecular Sequence Data
- Humans
- Hemoglobinopathies
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Transcription, Genetic
- Transcription Factors
- Sp1 Transcription Factor
- Simian virus 40
- Regulatory Sequences, Nucleic Acid
- Oligonucleotide Probes
- Mutation
- Molecular Sequence Data
- Humans
- Hemoglobinopathies