Novel mutations in the VKORC1 gene of wild rats and mice – a response to 50 years of selection pressure by warfarin?

Rost, S.; Pelz, Hans-Joachim; Menzel, Sandra; MacNicoll, Alan; León, Vanina; Song, Ki Joon; Jäkel, Thomas; Oldenburg, Johannes; Müller, C. R.

doi:10.1186/1471-2156-10-4

Cited by 134 publications

(227 citation statements)

References 27 publications

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“…Specifically, only 10 and 14 polymorphic synonymous and non-synonymous SNPs, respectively, were observed in the original data on SNP variation in the Norway rat [7]. Synonymous and non-synonymous divergent sites, however, were not observed (Additional file 1).…”

Section: Resultsmentioning

confidence: 99%

“…possible R. rattus or R. rattus -like) species origin in the published data [7]. Questionable origin of SNPs was judged based on the results of phylogenetic analysis (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…[7] and R. losea [8]. Moreover, SNPs in both the coding and 5' non-coding regions of the gene are associated with warfarin (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

“…When mutated, it was shown that this position confers resistance in vivo and in vitro [7,14]. However, as evidenced from alignments among Drosophila , fish and mammals, the vkorc1 gene is highly conserved.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

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BackgroundCertain mutations in the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) mediate rodent resistance to warfarin and other anticoagulants. Testing for resistance often involves analysis of the vkorc1. However, a genetic test for the roof rat (Rattus rattus) has yet to be developed. Moreover, an available roof rat vkorc1 sequence would enable species identification based on vkorc1 sequence and the evaluation of natural selection on particular vkorc1 polymorphisms in the Norway rat (R. norvegicus).ResultsWe report the coding sequence, introns and 5' and 3' termini for the vkorc1 gene of roof rats (R. r. alexandrinus and R. r. frugivorus) from Uganda, Africa. Newly designed PCR primers now enable genetic testing of the roof rat and Norway rat. Only synonymous and noncoding polymorphisms were found in roof rats from Uganda. Both nominal subspecies of roof rats were indistinguishable from each other but were distinct from R. losea and R. flavipectus; however, the roof rat also shares at least three coding sequence polymorphisms with R. losea and R. flavipectus. Many of recently published vkorc1 synonymous and non-synonymous single nucleotide polymorphisms (SNPs) in Norway rats are likely SNPs from roof rats and/or other Rattus species. Tests applied to presumably genuine Norway rat vkorc1 SNPs are consistent with a role for selection in two populations carrying the derived Phe63Cys and Tyr139Cys mutations.ConclusionGeographic mapping of vkorc1 SNPs in roof rats should be facilitated by our report. Our assay should be applicable to most species of Rattus, which are intermediate in genetic distance from roof and Norway rats. Vkorc1-mediated resistance due to non-synonymous coding SNPs is not segregating in roof rats from Uganda. By using the roof rat sequence as a reference vkorc1, SNPs now can be assigned to the correct rat species with more confidence. Sampling designs and genotyping strategies employed so far have helped detect candidate mutations underlying vkorc1-mediated resistance, but generally provided unsuitable data to test for selection. We propose that our understanding of vkorc1-mediated evolution of resistance in rodents would benefit from the adoption of sampling and genotyping designs that enable tests for selection on vkorc1.

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Section: Resultsmentioning

confidence: 99%

“…possible R. rattus or R. rattus -like) species origin in the published data [7]. Questionable origin of SNPs was judged based on the results of phylogenetic analysis (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…[7] and R. losea [8]. Moreover, SNPs in both the coding and 5' non-coding regions of the gene are associated with warfarin (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

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“…Rost et al reported that HEK293 cells which overexpressed mutated VKORC1 (Tyr139Cys) had lower VKOR activity than that of wild-type cells, even in the absence of warfarin [12]. However, activity of the mutant VKOR was not inhibited by warfarin.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in VKORC1 and Its Effect on Enzymatic Activity in Japanese Warfarin-Resistant Rats

et al. 2013

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ABSTRACT. Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 µM. The V max values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The K m values of resistant rats (47 ± 32 µM) were similar to those of sensitive rats (59 ± 18 µM). Warfarin-sensitive rats exhibited enzyme efficiencies (V max /K m ) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.

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