House mouse

A dominant autosomal warfarin-resistance gene was determined on chromosome 7 in house mice. Three VKORC1 sequence variants mediating resistance to anticoagulants seem to be widely distributed: Tyr139Cys (Y139C), Leu128Ser (L128S) and a group of linked sequence variants Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu (spretus introgression).

House mice carrying the homozygous Y139C sequence variant were found to be highly resistant to warfarin and bromadiolone.

Research in the UK with a strain of house mice carrying the homozygous Leu128Ser sequence variant showed such mice to be resistant to warfarin, and presumably other first-generation anticoagulants. Some individuals also survived choice and no-choice trials with bromadiolone and difenacoum. It seems that the mutation enables some of the mice to stabilize their vitamin K metabolism even when consuming anticoagulants of high potency over prolonged periods.

The third VKORC1 sequence variant (Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu) has probably been transferred from Mus spretus, a species found in the Iberian peninsula and north Africa, to Mus musculus by inter-specific hybridisation and then quickly spread over long distances, presumably by freight transportation of individuals. Although the phenotypic effect must still be verified, it is known to be associated with a substantial loss of anticoagulant efficacy against first-generation anticoagulants (e.g. warfarin, coumatetralyl), as well as the second-generation compounds bromadiolone and most probably difenacoum.

Studies revealed that sex and modifier genes, which influence the expression of the resistance gene, affect the penetrance of the genotype in house mice. Variations in metabolism and clearance are also known to influence the efficacy of anticoagulants, probably associated with detoxification by the enzyme complex cytochrome P450.

Table 3a: One of the most important polymorphisms of the VKOR proven to induce resistance to anticoagulants in the house mouse (Mus musculus), and resistance factors in male and female resistant mice, based on BCR data. Also given are the ED50 values for males and females in mg/kg bodyweight of the susceptible baseline strain. The data in this table are the result of work funded by RRAC and conducted by Dr C Prescott and Ms Mhairi Stevens (the University of Reading, UK).

VKOR Resistance Factors in male/female homozygous house mice
Susceptible strain ED50: (males/females) Bromadiolone Difenacoum Brodifacoum Flocoumafen Difethialone
1.96 / 1.68 0.85 / 0.56 0.39 / 0.35 0.51 / 0.44 0.83 / 0.83
Y139C 17 / 21 1.2 / 2.7 1.7 / 1.9 0.9 / 1.2 1.5 / 1.5

Table 3b: Resistance Factors to first generation anticoagulant rodenticides in the Y139C homozygous mouse strain.  Data were provided by Prescott, Baxter, Coan, Jonses, Rymer and Buckle (University of Reading).

VKOR Resistance Factors in male/female homozygous mice
Susceptible strain ED50: (males/females) Chlorphacinone Coumatetralyl Diphacinone Warfarin Sodium
0.86 / 0.86 1.95 / 5.02 0.91 / 0.91 1.50 / 1.50
Y139C 628 / 628 32 / 21 539 / 539 275 / 534

Table 5: Polymorphisms of the VKOR proven to induce resistance to warfarin in the house mouse (Mus musculus), and compounds recommended to control them (+). Mouse strains resist those compounds are marked with (-).

VKOR Polymorphism Compounds recommended (+) and not recommended (-) for control
Strain First-generation anticoagulants Bromadiolone Difenacoum Brodifacoum Flocoumafen Difethialone
L120Q no data available + + +
L128S - - + + + +
Y139C - - + + + +
Y139S no data available + + +
R12W/A26S/ A48T/R61L (spretus-Introgression strain) - - - + + +