The molecular basis of type 1von Willebrand disease.

Von Willebrand factor (VWF) is a plasma glycoprotein that acts as a carrier for factor VIII in the circulation and mediates both the adhesion and aggregation of platelets at sites of vessel injury, particularly under conditions of high shear. Defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. In type 1 VWD, the most common VWD subtype, VWF structure is normal but plasma and/or platelet VWF levels are reduced to approximately 20-50% of normal. Inheritance of type 1 VWD is autosomal dominant with reduced penetrance and variable expression. Few molecular defects have been identified in type 1 VWD patients. This dissertation examines the molecular pathogenesis of type 1 and type 3 VWD in a pedigree and investigates the genetic basis for a mouse model of type 1 VWD. A proband with type 3 VWD is shown to be homozygous for a previously reported single nucleotide deletion in VWF exon 18, $\Delta$C2685. The phenotype in heterozygotes is observed to range from normal to type 1 VWD. Although this frameshift mutation results in proximal premature termination of VWF translation, the abnormal VWF mRNA is stable. The mutant truncated recombinant VWF protein is retained within transfected cells, and no propeptide processing is observed. Cotransfection of mutant and wild-type recombinant VWF fails to demonstrate a dominant effect of the mutant on the normal allele. The dissertation next focuses on characterization of a mouse model for type 1 VWD, the inbred mouse strain RIIIS/J. Among progeny from crosses between RIIIS/J and the PWK or CASA/Rk strains, the distributions of VWF levels suggest the presence of a major autosomal dominant gene for low VWF levels. Analysis of intragenic polymorphisms excludes the Vwf locus as a significant determinant of VWF level in RIIIS/J mice. The major novel locus, Mvwf, for modifier of VWF, maps to an approximately 0.5 centimorgan interval on chromosome 11, between nerve growth factor receptor (Ngfr) and the homeobox b (Hoxb) cluster, nonrecombinant with gastric inhibitory peptide (Gip). A contig of isolated yeast artificial chromosomes and genomic P1 clones partially cover the Mvwf region. The contig contains a glycosyltransferase, the N-acetylgalactosamine transferase Ctnac, a strong candidate for the Mvwf gene. Characterization of the human homologue of Mvwf could identify an important modifying factor for VWD penetrance and expressivity in humans. Together, these studies illustrate two fundamental mechanisms contributing to the clinical expression of type 1 VWD: inactivating mutations in the VWF gene and alterations in modifying genes that also contribute to the determination of plasma VWF level.PhDHuman GeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105127/1/9635575.pdfDescription of 9635575.pdf : Restricted to UM users only