Modifier of von Willebrand Factor-1, a Model of Type 1 von Willebrand Disease (VWD)
The regulation of endothelial cell gene expression plays a central role in maintaining hemostatic balance, and we are just beginning to understand the key sequence elements responsible for the control of the endothelial gene expression program. The inbred mouse strain, RIIIS/J, was found to have an endothelial-specific regulatory mutation in the gene encoding an N-acetylgalactosaminyltransferase, B4GALNT2. This regulatory mutation, termed Mvwf1, directs a tissue-specific switch in the B4galnt2 gene expression program from intestinal epithelium to vascular endothelium. The endothelial expression of B4GALNT2 results in aberrant glycosylation of VWF and accelerated VWF clearance from circulation, causing a phenotype very similar to Type 1 VWD in humans. The ectopic expression of B4galnt2 in vascular endothelial cells results in aberrant post-translational modification of VWF, leading to accelerated clearance. We seek to characterize the mutation responsible for this remarkable tissue-specific switch in gene expression. Using comparative sequence analysis and BAC transgenic studies we have identified a genomic region distal to the B4galnt2 structural gene that likely contains the regulatory elements necessary for tissue-specific B4galnt2 gene expression. We are recombineering BACs to pinpoint the regions critical for endothelial cell-specific gene regulation for further study. During the course of these studies we also found that Mvwf1 exists in some contemporary wild mouse populations and have found evidence that this low-VWF Mvwf1 phenotype could be maintained due to selective pressure. We are now investigating if there are other phenotypes resulting from Mvwf1 that could affect reproductive fitness in natural populations.

Familial Idiopathic Thrombocytopenic Purpura (ITP)
Idiopathic thombocytopenic purpura (ITP) is defined by the presence of thrombocytopenia in the absence of an identifiable secondary cause. An autoimmune process has been strongly implicated, yet the molecular mechanisms responsible for ITP are unknown and treatment remains largely empiric. Although ITP is generally considered a sporadic disorder, the possibility that there can be a familial predisposition to isolated ITP has been raised. Associations between ITP and polymorphisms in genes involved in immune response have been described, but these associations have not been proven causative. Rarely, ITP is associated with other autoimmune cytopenias, but the etiology of associated cytopenias is also unknown, and therapy is similar to the management of isolated ITP. Our goal is to identify gene(s) involved in the pathogenesis of familial ITP. We initiated this study when we were contacted about a large family with familial ITP, and several family members also have autoimmune hemolytic anemia. We aim to study this family and recruit similarly affected families in order to identify candidate genes involved in ITP. We speculate that genes identified in this study could be involved in key pathways involved in humoral immunity and the regulation of tolerance, but platelet-specific phenotypes or novel genes with previously unknown function may also be discovered.