Nucleic Acids Research, 1988, Vol. 16, No. 16 7783-7797
© 1988
Articles |
The effects of HPFH mutations in the human 
-globin promoter on binding of ubiquitous and erythroid specific nuclear factors
Dipartimento di Genetica e di Biologia dei Microrganismi, Università di Milano Studio Milan Milan, Italy 1Centro per lo Studio della Patologia Cellulare del CNR Milan, Italy
Received July 6, 1988. Accepted July 22, 1988.
Genetic evldence Indicates that single point mutations in the 
-globin promoter may be the cause of high expression of the mutated gene in the adult period (Hereditary Persistence of Fetal Hemoglobin, HPFH). Here we show that one of these mutations characterized by a T > C substitution at position 175 in a conserved octamer (ATGCAAAT) sequence, abollshes the ability of a ubiquitous octamer binding nuclear protein to bind a -globln promoter fragment containing the mutated sequence: however, the ability of two erythroid specific proteins to bind the same fragment is increased three to five fold. DMS Interference and binding experiments with mutated fragments indicate that the ubiquitous protein recognizes the octamer sequence, while the erythrold specific proteins B2, B3 recognize flanking nucieotldes. Competition experiments indicate that protein B2 corresponds to an erythrold-specific protein known to bind to a consensus GATAG sequence present at several locations In 
ß and -globin genes. Although the distal CCAAT box region oil the -globin gene shows a related sequence, an oligonucleotide Including this sequence does not show any ability to bind the above mentioned erythroid protein; Instead, It binds a different erythrold specific protein, in addition to a ubiquitous protein. The -117 G > A mutation also known to cause HPFH, and mapping two nucleotides upstream from the CCAAT box, greatly decreases the binding of the erythrold-specific, but not that oil the ubiquitous protein, to the CCAAT box region fragment.
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