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

Simone Rost, Hans Joachim Pelz, Sandra Menzel, Alan D. MacNicoll, Vanina León, Ki-Joon Song, Thomas Jäkel, Johannes Oldenburg, Clemens R. Müller

Research output: Contribution to journalArticle

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Abstract

Background: Coumarin derivatives have been in world-wide use for rodent pest control for more than 50 years. Due to their retarded action as inhibitors of blood coagulation by repression of the vitamin K reductase (VKOR) activity, they are the rodenticides of choice against several species. Resistance to these compounds has been reported for rodent populations from many countries around the world and poses a considerable problem for efficacy of pest control. Results: In the present study, we have sequenced the VKORC1 genes of more than 250 rats and mice trapped in anticoagulant-exposed areas from four continents, and identified 18 novel and five published missense mutations, as well as eight neutral sequence variants, in a total of 178 animals. Mutagenesis in VKORC1 cDNA constructs and their recombinant expression revealed that these mutations reduced VKOR activities as compared to the wild-type protein. However, the in vitro enzyme assay used was not suited to convincingly demonstrate the warfarin resistance of all mutant proteins Conclusion: Our results corroborate the VKORC1 gene as the main target for spontaneous mutations conferring warfarin resistance. The mechanism(s) of how mutations in the VKORC1 gene mediate insensitivity to coumarins in vivo has still to be elucidated.

Original languageEnglish
Article number4
JournalBMC Genetics
Volume10
DOIs
Publication statusPublished - 2009 Feb 6

Fingerprint

Warfarin
Coumarins
Pest Control
Pressure
Mutation
Rodent Control
Rodenticides
NAD(P)H Dehydrogenase (Quinone)
Genes
Enzyme Assays
Blood Coagulation
Missense Mutation
Mutant Proteins
Mutagenesis
Anticoagulants
Rodentia
Complementary DNA
Population
Proteins
Coumarin Resistance

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Novel mutations in the VKORC1 gene of wild rats and mice - A response to 50 years of selection pressure by warfarin? / Rost, Simone; Pelz, Hans Joachim; Menzel, Sandra; MacNicoll, Alan D.; León, Vanina; Song, Ki-Joon; Jäkel, Thomas; Oldenburg, Johannes; Müller, Clemens R.

In: BMC Genetics, Vol. 10, 4, 06.02.2009.

Research output: Contribution to journalArticle

Rost, Simone ; Pelz, Hans Joachim ; Menzel, Sandra ; MacNicoll, Alan D. ; León, Vanina ; Song, Ki-Joon ; Jäkel, Thomas ; Oldenburg, Johannes ; Müller, Clemens R. / Novel mutations in the VKORC1 gene of wild rats and mice - A response to 50 years of selection pressure by warfarin?. In: BMC Genetics. 2009 ; Vol. 10.
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