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DNA sequence variation in a negative control region 5' to the beta- globin
gene correlates with the phenotypic expression of the beta s mutation
J Elion, PE Berg, C Lapoumeroulie, G Trabuchet, M Mittelman, R Krishnamoorthy, AN Schechter and D Labie
INSERM Unite 120, Hopital Robert Debre, Paris, France.
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 beta-globin
gene that acts as a silencer for the transcription of this gene and have
shown that a polymorphism in this sequence is associated with a thalassemic
phenotype of the beta-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 beta s allele. It
was found that specific configurations of the motif, (AT)x(T)y, are
homogeneous for the major haplotypes of the beta-globin gene cluster
described on beta s chromosomes. Binding of BP1 was measured to DNA of
three haplotypes: Indian, Benin, and Bantu. BP1 binds most tightly to DNA
of the Indian haplotype, and these patients produce less beta s protein
than Benin patients, whose DNA exhibits weaker affinity for BP1. Binding of
BP1 is the weakest to DNA of the Bantu haplotype, which is associated with
clinically more severe sickle cell symptoms. These data are consistent with
the hypothesis that these polymorphisms may not be neutral and that the DNA
sequence at this site may affect the expression of the beta s gene. Such an
effect may be synergistic with other genetic variables, such as fetal
hemoglobin levels, F-cell numbers, and the number of alpha-globin genes, in
determining intracellular polymerization and, thus, the severity of the
sickle cell syndromes.
Volume 79,
Issue 3,
pp. 787-792,
02/01/1992
Copyright © 1992 by The American Society of Hematology
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