DNA Sequence Variation in a Negative Control Region 5 ’ to the p - Globin Gene Correlates With the Phenotypic Expression of the pS Mutation

The clinical diversity of sickle cell anemia is strongly related to the degree of intracellular hemoglobin S (Hb S) polymerization, which in turn is dependent on the intracellular concentration of Hb S. We have recently defined a region of DNA approximately 500 bp 5‘ to the human p-globin gene that acts as a silencer for the transcription of this gene and have shown that a polymbrphism in this sequence is associated with a thalassemic phenotype of the B-globin gene. In this work we have examined the correlation of DNA sequence polymorphisms in this silencer with binding of a previously identified putative repressor protein, BP1, and with the expression of Hb S in individuals heterozygous for the p’ allele. It was found that specific configurations of the motif, (AT)x(T)y, are homogeneous for the major haplotypes of the p-globin gene cluster described on p’ chromosomes. Binding