The human platelet alpha IIb gene is not closely linked to its integrin partner beta 3

alpha IIbb3 integrin is a heterodimeric receptor facilitating platelet aggr egation. Both genes are on chromosome 17q21.32, Intergenic distance between them has been reported to be 125 to 260 kilobasepairs (kb) by pulsed-field gel electrophoresis (PFGE) genomic analysis, suggesting that they may be r egulated coordinately during megakaryopoiesis, In contrast, other studies s uggest these genes are greater than 2.0 megabasepairs (mb) apart. Because o f the potential biological implications of having these two megakaryocytic- specific genes contiguous, we attempted to resolve this discrepancy. Taking advantage of large kindreds with mutations in either alpha IIb or beta 3, we have developed a genetic linkage map between the thyroid receptor hormon e-1 gene (THRA1) and beta 3 as follows: cen-THRA1-BRCA1-D17S579/alpha IIb-b eta 3-qter with a distance of 1.3 centiMorgans (cM) between alpha IIb and b eta 3 and the two genes being oriented in the same direction. PFGE genomic and YAC clone analysis showed that the beta 3 gene is distal and greater th an or equal to 365 kb upstream of alpha IIb. Additional restriction mapping shows alpha IIb is linked to the erythrocyte band 3 (EPB3) gene, and beta 3 to the homeobox HOX2b gene. Analysis of alpha IIb(+)-BAC and P1 clones co nfirm that the EPB3 gene is similar to 110 kb downstream of the alpha IIb g ene, Sequencing the region surrounding the human alpha IIb locus showed the Granulin gene similar to 18 kb downstream to alpha IIb, and the KIAA0553 g ene similar to 5.7 kb upstream. This organization is conserved in the murin e sequence. These studies show that alpha IIb and beta 3 are not closely li nked, with alpha IIb flanked by nonmegakaryocytic genes, and imply that the y are unlikely to share common regulatory domains during megakaryopoiesis. (C) 1999 by The American Society of Hematology.