Allele-dependent transcriptional regulation of the human integrin alpha(2)gene

Genetically controlled variation in alpha (2)beta (1) expression by human b lood platelets was previously described. Sixty-two haplotype sequences corr esponding to the proximal 5' regulatory region (-1096 to +1) of the alpha ( 2) gene were compared, and a dimorphic sequence -52C>T was identified that is located precisely between 2 tandem Sp1/Sp3 binding elements previously s hown to be absolutely required for transcriptional activity of this gene in epithelial cell lines and the erythroleukemic cell line K562, The gene fre quency of -52T in a random Caucasian population is approximately 0.35, and the expression of -52T correlates directly with reduced densities of platel et alpha (2)beta (1) In mobility shift analyses, the -52T substitution atte nuates complex formation with both Sp1 and Sp3, When transfected into the e rythroleukemia cell line Dami, promoter-luciferase constructs bearing the - 52T sequence exhibit a 5-fold decrease in activity relative to the -52C con struct, In transfected CHRF-288-11 megakaryocytic cells, the corresponding activity decreases by 10-fold, The -52T sequence appears to be in linkage d isequilibrium with the previously defined allele A3 (807C; HPA-5b), known t o be associated with diminished expression of platelet alpha (2)beta (1) In summary, a natural dimorphism has been identified within the proximal 5' r egulatory region of the human integrin alpha (2) gene that is responsible f or decreased expression levels of the integrin alpha (2)beta (1) on blood p latelets through a mechanism that is probably mediated by the nuclear regul atory proteins Sp1 and Sp3.(Blood. 2001; 97:1721-1726) (C) 2001 by The Amer ican Society of Hematology.