International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 128 - A SENSITIZED ENU MUTAGENESIS SCREEN FOR DOMINANT GENETIC MODIFIERS OF THROMBOSIS IN THE FACTOR V LEIDEN MOUSE

Westrick R J
University of Michigan

Co-Authors: 1) Manning S L, 2) Aiyagari A, 2) Siemieniak D R, 1) Korepta L M, 1,2) Ginsburg D
Institutions: 1) University of Michigan, 2) Howard Hughes Medical Institute

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 candidates for the modifier genes 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. Male FvQ/Q mice were mutagenized with a single ENU dose of 150mg/kg 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 1443 G1 offspring thus far has identified 11 mice that survived to weaning. Of the two mutants progeny tested to date, one appears 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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