International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 48 - A SENSITIZED ENU MUTAGENESIS SCREEN FOR DOMINANT GENETIC MODIFIERS OF THROMBOSIS IN THE FACTOR V LEIDEN MOUSE

Westrick RJ 1, Manning SL 2, Dobies SL 1, Peterson AL 2, Siemieniak DR 2, Korepta LM 1, Ginsburg D 2

1 University of Michigan, Ann Arbor, United States, 2 Howard Hughes Medical Institute, Ann Arbor, United States

Venous thrombosis affects ~300,000 individuals per year in the USA.  A gain-of-function mutation in the factor V gene, Factor V Leiden, (FVL) is the most common known inherited risk factor for venous thrombosis.  Penetrance is incomplete, with only ~10% of FVL individuals experiencing clinically significant thrombosis.  We are performing a whole genome mouse mutagenesis screen to identify modifier gene candidates contributing to the penetrance of FVL in humans.  Previously, we demonstrated synthetic lethality between FVL and genetic deficiency of a key coagulation component, tissue factor pathway inhibitor (TFPI).  Complete TFPI deficiency in mice is embryonic lethal, whereas heterozygosity is compatible with normal survival.  However, homozygosity for FVL (FvQ/Q) in the context of heterozygosity for TFPI (Tfpi+/-) is uniformly lethal due to disseminated perinatal thrombosis.  This synthetic lethal interaction was utilized as a phenotyping tool for a sensitized ENU mutagenesis screen.  We aim to uncover novel dominant mutations that improve hemostatic balance leading to survival of FvQ/Q Tfpi+/- mice.  We have proven our approach by rescuing FvQ/Q Tfpi+/- with tissue factor (Tf+/-) heterozygosity.  Male FvQ/Q mice were ENU mutagenized and bred to FvQ/+ Tfpi+/- double heterozygous females.  Surviving G1 offspring were analyzed to identify rescued mice with the FvQ/Q Tfpi+/- genotype.  Analysis of 2199 G1 offspring thus far has identified 15 mice that survived to weaning.  Of the 8 mutants progeny tested to date, 3 appear to be heritable.  Our preliminary findings demonstrate the feasibility of our sensitized approach in the identification of dominant suppressors of the FvQ/Q Tfpi+/- lethal phenotype.

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