Submitted April 5, 2006
Accepted June 25, 2006
Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene
Heidi L Lemmerhirt, Jordan A Shavit, Gallia G Levy, Suzanne M Cole, Jeffrey C Long, and David Ginsburg*
The University of Michigan, Ann Arbor, MI, USA
* Corresponding author; email: ginsburg{at}umich.edu.
Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for ~16% of the 8-fold plasma VWF variation (or ~25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated non-synonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain-of-function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.
