MDR1 Mutation in Collies

MDR1 Mutation Results in Drug Side Effects for Collies

What is the MDR1 Mutation and How Does It Impact Collies?

The MDR1 gene produces P-glycoprotein. P-glycoprotein acts as the gatekeeper between blood and the central nervous system protecting the brain and central nervous system from toxin accumulation. The MDR1 mutation (MDR1-1) results in an absence of functioning P-glycoprotein. Collies and other canine breeds affected by this mutation are unable to filter toxins present in specific drug therapies used in veterinary medicine.
Big image

History and Distribution

  • Collie sensitivity to the drug Ivermectin is recognized in the early 1980's.
  • The mutation is identified in several countries and across breeds related to the collie including mix-breed dogs.
  • DNA analysis shows all dogs with the mutation descend from a dog (breed undefined) living in the United Kingdom in the 1800's.

Distribution

Big image
Big image

Problems Associated with MDR1-1

  • Complications including excessive salivation, ataxia, respiratory distress, coma, and death arise in use of drug therapies for mange, heartworm, fleas and ticks, as well as some anesthesia.
  • Drug therapy ingestion occurs accidentally after consumption of feces from treated large animals as a result of lack of awareness in some agricultural settings.
  • Diagnosis requires genotyping PRIOR to drug therapy.
  • Treatment after ingestion includes activated charcoal, symptomatic, and support care.

Risks Levels Associated with Drug Therapies in Collies

Big image

Video Displaying MDR1 Mutation Phenotype after Drug Therapy in a Mixed Breed

Ginger's Story

Genetic Transmission

  • MDR1-1 is autosomal recessive and is not sex-linked.
  • MDR1-1 is the result of a four base pair deletion on chromosome 14.
  • The four base pair deletion results in a frame shift and a premature stop codon.

Genotypes

  • The dominant allele is MDR1, +, or Normal.
  • The recessive allele is MDR1-1, -, or Mutant.
  • Genotypes are at right; ++ (normal), +- (carrier), and --(mutant).
  • There is evidence that heterozygotes (carrier) may experience some degree of drug sensitivity with faster recovery, indicating partial dominance.

Breeding

  • There is no phenotypic evidence of mutation prior to exhibition of symptoms during and after drug therapy (see Ginger's Story video).
  • DNA test for the MDR1-1 Mutation prior to breeding.
  • Testing uses a simple cheek swab and costs approximately $70.00.



Opinion

  • Education offered by all small and large animal veterinarians catches both pet and working dog owner populations. Responsible owners can test for MDR1-1 at any age and tag their dogs if the mutation is present. Practicing minimum dosage and proper application of drug therapies reduces phenotypic expression. Breeders using MDR1 homozygous normal genotype based selection for breeding reduce allele frequency. Elimination of MDR1-1 homozygous recessive mutants and heterozygote carriers from breeding programs as populations allow will assist in eliminating the mutation.
  • Question

    Due to small populations, breeders of some collie related breeds cannot eliminate carriers and mutants without losing other desirable traits. Should breeders be required by governing bodies (clubs and associations) to eliminate mutants and carriers altogether or should greater emphasis be placed on development of less toxic drug therapies for all canines?

    References

    1. GEYER, J., DÖRING, B., GODOY, J. R., LEIDOLF, R., MORITZ, A. and PETZINGER, E. (2005), Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany. Journal of Veterinary Pharmacology and Therapeutics, 28: 545–551. doi: 10.1111/j.1365-2885.2005.00692.x . Web 21 April 2013. http://onlinelibrary.wiley.com.ezproxy.proxy.library.oregonstate.edu/doi/10.1111/j.1365-2885.2005.00692.x/full
    2. Irina Gramer, Regina Leidolf, Barbara Döring, Stefanie Klintzsch, Eva-Maria Krämer, Ebru Yalcin, Ernst Petzinger, Joachim GeyerBreed distribution of the nt230(del4) MDR1 mutation in dogsThe Veterinary Journal, Volume 189, Issue 1, July 2011, Pages 67–7. Web 21 April 2013. http://dx.doi.org/10.1016/j.tvjl.2010.06.012 http://www.sciencedirect.com.ezproxy.proxy.library.oregonstate.edu/science/article/pii/S1090023310002261
    3. Joachim Geyer, Christina Janko. Treatment of MDR1 Mutant Dogs with Macrocylic Lactones. Curr Pharm Biotechnol. 2012 May, 13(6): 969-986. doi: 10.2174/138920112800399301. Web 21 April. 2013. http://www.eurekaselect.com/96885/article
    4. The Smooth Collie Club of Great Britain. http://www.smoothcollieclub.com/09mdr.htm. 2011. Web 21 April 2013.
    5. Washington State University. "Multidrug Sensitivity in Dogs." http://www.vetmed.wsu.edu/depts-VCPL/index.aspx. Veterinary Clinical Pharmacology Lab. 2013. Web 21 April. 2013.