International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Lemmerhirt HL 1, Ginsburg D 2

1 Department of Human Genetics, The University of Michigan, Ann Arbor, United States, 2 Howard Hughes Medical Institutue, Ann Arbor, United States

Circulating levels of von Willebrand factor (VWF), a blood coagulation protein, vary greatly among human and inbred mouse populations.  Both the Vwf gene and secondary modifier genes are critical in VWF level regulation. One murine modifier gene we previously reported, Mvwf1, lowers VWF levels in a subset of inbred mouse lines.  To identify modifier genes affecting Mvwf1-independent strains, we examined 200 F2 mice from an A/JxCASA/Rk cross. A pooled genome scan found VWF levels strongly correlated with parental genotype at markers D6Mit12 and D9Mit67.  D6Mit12 is closely linked (1.2 cM) to murine Vwf, suggesting strain-specific differences in Vwf expression or protein structure may be partly responsible for the variation observed.  Sequence analysis of Vwf mRNA identified 20 SNPs between these strains, four that encode amino acid changes.  F1 Vwf mRNA analysis does not suggest strain-specific differences in allele expression.  Allelic differences in protein biosynthesis and secretion are being examined through transfection analysis of A/J and CASA/Rk Vwf cDNAs.  Specific candidate genes at the D9Mit67 locus have not yet been characterized.  Collectively, D6Mit12 and D9Mit67 account for ~23% of the VWF level difference observed between these strains.  To identify additional modifier loci contributing to the substantial remaining variation, we are now conducting an extended non-pooled genome scan using all 200 F2 mice.  These data, when combined with our earlier results, should provide novel insight into the genetic complexity of VWF level regulation in mice and may help identify candidates for modifiers of bleeding and thrombotic risk in humans.

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