Genetic Modifiers of Venous Thrombosis: Rescue of a Lethal Genotype
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Venous Thrombosis affects 1 in 1000 individuals every year. Research indicates that there are many factors, both genetic and environmental, that contribute to the pathologic symptoms attributed to the disease. Several mutations and polymorphisms in genes that encode for blood coagulation factors have been shown to lead to venous thrombosis. Among the most influential are Factor V (FV) and Tissue Factor Pathway Inhibitor (TFPI). Judging from the incomplete penetrance of many of these factors, we presume that there are many unknown modifier genes. We set out to create a mouse model that will help us elucidate those genes. Our model focuses on inducing mutations in mice that have an altered genotype, one that is normally lethal due to thrombosis. This genotype is the combination of a homozygous mutation in the Factor Five gene called the Factor Five Leiden mutation as well as a mutation in the Tissue Factor Pathway Inhibitor gene that causes a 50% reduction in the TFPI protein, this genotype will be referred to as FVL (Q/Q) TFPI (+/-). In order to identify modifier genes to venous thrombosis this lethal genotyped will be bred into mice that have random mutations throughout their genome. Any living mouse will have a suppressing gene that rescues the lethal genotype. The region of the genome responsible for the suppression will be isolated by mating strategies, as well as whole genome single nucleotide polymorphism screening. Using whole genome mutagenesis, we have successfully induced mutations in the mouse genome that allow a rescue; we have also found a rescuing mutation in the DBA mouse strain genome. To date we have established a successful mouse model and have rescued over 500 mice with this lethal genotype. We are currently close to isolating these regions, as data collection and analysis are still in progress.