The Human Platelet IIb Gene Is Not Closely Linked to Its Integrin Partner β3

Abstract

AbstractIIbb3 integrin is a heterodimeric receptor facilitating platelet aggregation. 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 regulated coordinately during megakaryopoiesis. In contrast, other studies suggest these genes are greater than 2.0 megabasepairs (mb) apart. Because of 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 IIb or β3, we have developed a genetic linkage map between the thyroid receptor hormone-1 gene (THRA1) and β3 as follows: cen-THRA1-BRCA1-D17S579/IIb-β3-qter, with a distance of 1.3 centiMorgans (cM) between IIb and β3 and the two genes being oriented in the same direction. PFGE genomic and YAC clone analysis showed that the β3 gene is distal and ≥365 kb upstream of IIb. Additional restriction mapping shows IIb is linked to the erythrocyte band 3 (EPB3) gene, and β3 to the homeobox HOX2b gene. Analysis of IIb+-BAC and P1 clones confirm that the EPB3 gene is ∼110 kb downstream of the IIb gene. Sequencing the region surrounding the human IIb locus showed the Granulin gene ∼18 kb downstream to IIb, and the KIAA0553 gene ∼5.7 kb upstream. This organization is conserved in the murine sequence. These studies show that IIb and β3 are not closely linked, with IIb flanked by nonmegakaryocytic genes, and imply that they are unlikely to share common regulatory domains during megakaryopoiesis.