HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Genetic deletion of mouse platelet glycoprotein Ib produces a Bernard-Soulier phenotype with increased -granule size

Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ib subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ib subunit, GP Ib Null mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ib Null genotype revealed -granules with increased size as compared with the -granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger -granules in the GP Ib Null platelet. The SEPT5 gene resides approximately 250 nucleotides 5 to the GP Ib gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ib coding sequences as a result in an imperfect polyadenylation signal within the 3 end of both the human and mouse SEPT5 genes. We observed a 2to 3-fold increase in SEPT5 protein levels in platelets from GP Ib Null mice. These results implicate SEPT5 levels in the maintenance of normal -granule size and may explain the variant granules associated with human GP Ib mutations and the Bernard-Soulier syndrome. (Blood. 2004;104:2339-2344)