International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Plenary Presentations * Oral Presentations *
Poster Presentations: Complex Genetics and Disease Modifiers * Developmental Genetics * Functional Genomics * Gene Discovery * Genetic Manipulations to Alter Gene Function * Mouse Models: Human Disease and Pharmacogenetics * Sequence Annotation and Comparative Analysis of Genomes *
Attendees * Sponsors * Table of Contents * Photographs * Awards

POSTER 25 - IDENTIFICATION OF GENETIC MODIFIERS INFLUENCING CIRCULATING PLASMA VON WILLEBRAND FACTOR LEVELS IN MICE

H Rottschafer
The University of Michigan

Ginsburg D
Howard Hughes Medical Institute at The University of Michigan

Levels of circulating plasma von Willebrand factor (VWF), a central protein in blood coagulation, are highly variable within both the human population and inbred mouse strains.  Our lab has previously reported the identification of a genetic modifier of VWF levels in mice which causes a tissue-specific switch in the expression of a glycosyltransferase (Galgt2), resulting in accelerated VWF clearance from plasma.  To identify additional VWF modifier genes, a cross of A/J and CASA/Rk mice was performed.  VWF levels in these strains differ by seven-fold and are independent of the Galgt2 modification.  A genome scan of 200 F2 progeny found VWF levels strongly correlated with parental genotype at the D6Mit12 and D9Mit67 markers.  D6Mit12 is closely linked (~1.2 cM) to the murine Vwf gene, suggesting that strain-specific differences in VWF expression or protein structure may be partly responsible for the variation observed.  Sequence analysis of the 8.7 Kb Vwf mRNA from these strains revealed a total of 19 SNPs, 4 resulting in amino acid changes.  Analysis of F1 mRNA is consistent with equivalent gene expression from both alleles.  This result suggests a control mechanism involving strain-specific alterations in either VWF biosynthesis or clearance from plasma.  Fine mapping at the D9Mit67 locus is in progress, with no obvious candidate gene known to lie in this interval.  The characterization of VWF modifier genes in the mouse may provide novel insight into regulation of hemostatic balance and should also identify candidates for modifiers of bleeding and thrombotic risk in humans.