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Increased protein binding to a −530 mutation of the human β‐globin gene associated with decreased β‐globin synthesis
Author(s) -
Berg Patricia E.,
Mittelman Moshe,
Elion Jacques,
Labie Dominique,
Schechter Alan N.
Publication year - 1991
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.2830360109
Subject(s) - globin , microbiology and biotechnology , biology , gene , footprinting , thalassemia , mutation , fetal hemoglobin , regulatory sequence , binding protein , promoter , binding site , genetics , alpha globulin , electrophoretic mobility shift assay , regulation of gene expression , gene expression , transcription factor , fetus , pregnancy
Although some cases of the syndrome of hereditary persistence of fetal hemoglobin (HPFH) have been correlated with mutations causing a change in the binding of trans‐acting factors to DNA sequences flanking the γ‐globin gene, this mechanism has not been described in β‐thalassemias upstream of the canonical promoter of the β‐globin gene. In this report we describe such a change in binding of a protein that may explain a silent carrier phenotype of β‐thalassemia. We have previously demonstrated the binding of a protein (BP1) derived from a nuclear extract of human K562 cells to DNA 5′ to the human β‐globin gene in a region having a negative regulatory function. The binding of BP1 in this region can be detected by DNAse I footprinting and by gel mobility shift analysis. We have now compared binding of BP1 to the normal sequence and a mutated sequence (+ATA/‐T at −530 bp from the cap site) from the silent carrier of β‐thalassemia. Using mobility shift assays we show that BP1 binds about nine times more strongly to the mutated sequence than the normal sequence. These results suggest the possibility that the decreased expression of the β‐globin gene exhibited by the carrier may be due, at least in part, to tighter binding of a protein which functions as a negative control element or represser.