Multidrug Resistance 1

Other Names: Ivermectin sensitivity, MDR1 gene defect, Multidrug sensitivity, MDR1
Affected Genes: ABCB1
Inheritance: Autosomal Incomplete Dominant
Mutation: chr14:13726596-13726599 (canFam3): 4 bp deletion (del AGAT)

Add To Cart Search Tests

Common Symptoms

Multidrug resistance 1, also called MDR1, is an inherited condition affecting several breeds of dogs, especially herding dogs such as the white shepherd dog. The Mutation in the ABCB1 gene associated with MDR1 causes dysfunction of P-glycoprotein, which is responsible for removing certain drugs and toxins from the body. Clinical signs are most commonly associated with distribution of the drug in the central nervous system. MDR1 is inherited in an autosomal incomplete dominant manner in dogs meaning that dogs only need to inherit one copy of the mutated gene to be at an increased risk of developing adverse reactions to certain medications. Though adverse reactions to certain drugs are most commonly seen in dogs having two copies of the mutated gene, Carrier dogs can also experience drug sensitivities and dosages need to be adjusted accordingly. Thus, dogs that have one or two copies of the mutation are considered at-risk for adverse drug reactions. If an at-risk dog is treated with one of several common drugs (see below*), they are at risk of developing neurologic symptoms that could range from tremors, excess salivation, anorexia, and blindness to coma and even death. Because of the defective ability to metabolize specific drugs, these drugs can be lethal even at low doses. The MDR1 mutation does not cause adverse effects in dogs unless the dog is exposed to these drugs. Therefore, veterinarians should be notified when a dog is at risk for multidrug resistance 1 prior to administration of any medications.

*Drugs known to cause neurological signs related to the MDR1 mutation:
Acepromazine, butorphanol, doxorubicin, emodepside, erythromycin, ivermectin, loperamide, milbemycin, moxidectin, rifampin, selamectin, vinblastine and vincristine

In addition to this list, there are many other drugs known to be removed from the central nervous system via the P-glycoprotein mechanism in humans. However, reports of neurological dysfunction related to drugs other than those listed here are scarce in dogs. Please consult your veterinarian prior to giving drugs to known multidrug resistance 1 carriers, affected dogs, or untested dogs of breeds commonly affected with this condition.

Breed-Specific Information for the White Shepherd Dog

The Mutation of the ABCB1 gene associated with multidrug resistance 1 has been identified in the white shepherd dog. Though the exact frequency in the overall white shepherd dog population is unknown, 21.5% out of 219 white shepherd dogs from Germany, the Netherlands, Switzerland, and Austria had one copy of the mutation and 2.3% had two copies of the mutation, with an overall frequency of at risk dogs of 23.8%. In another study of 13 European countries, 31% out of 234 white shepherd dogs had one copy of the mutation and 0.8% had two copies of the mutation, with an overall frequency of at risk dogs of 31.8%. 

Testing Tips

Genetic testing of the ABCB1 gene in white shepherd dogs will reliably determine whether a dog is a genetic Carrier of multidrug resistance 1. Multidrug resistance 1 is inherited in an autosomal incomplete dominant manner in dogs meaning that dogs only need to inherit one copy of the mutated gene to be at an increased risk of developing the disease. Though adverse reactions to certain drugs are most commonly seen in dogs having two copies of the mutated gene, carrier dogs can also experience drug sensitivities and dosages need to be adjusted accordingly. Thus, dogs that have one or two mutant copies of the gene are considered at-risk for adverse drug reactions. When carriers of this Mutation are bred with another dog that also is a carrier of the same mutation, there is risk of having affected pups. For each pup that is born to this pairing, there is a 25% chance that the puppy will inherit two copies of the mutation and a 50% chance that the puppy will inherit one copy of the mutation and, in either case, may be susceptible to having adverse drug reactions. Reliable genetic testing is important for determining breeding practices. Because symptoms do not appear unless dogs are exposed to certain drugs, genetic testing should be performed before breeding. In order to eliminate this mutation from breeding lines and to avoid the potential of producing affected pups, breeding of known carriers is not recommended. White shepherd dogs that are not carriers of the mutation have no increased risk of having affected pups when bred to a dog that is also clear for this mutation.

There may be other causes of this condition in dogs and a normal result does not exclude a different mutation in this gene or any other gene that may result in a similar genetic disease or trait.

References

  • Alves L, Hulsmeyer V, Jaggy A, Fischer A, Leeb T, Drogemuller M. Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic border collies. J Vet Intern Med. 2011 May-Jun;25(3):484-9. [PubMed: 21488961]
  • Barbet JL, Snook T, Gay JM, Mealey KL. ABCB1-1 Delta (MDR1-1 Delta) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis. Vet Dermatol. 2009 Apr;20(2):111-4. [PubMed: 19171022]
  • Donner J, Kaukonen M, Anderson H, Moller F, Kyostila K, Sankari S, Hytonen M, Giger U, Lohi H. Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders. PLoS One. 2016 Aug 15;11(8):e0161005. [PubMed: 27525650]
  • Firdova Z, Turnova E, Bielikova M, Turna J, Dudas A. The prevalence of ABCB1:c.227_230delATAG mutation in affected dog breeds from European countries. Res Vet Sci. 2016 Jun;106:89-92. [PubMed: 27234542]
  • Geyer J, Klintzsch S, Meerkamp K, Wohlke A, Distl O, Moritz A, Petzinger E. Detection of the nt230(del4) MDR1 mutation in White Swiss Shepherd dogs: case reports of doramectin toxicosis, breed predisposition, and microsatellite analysis. J Vet Pharmcol Ther. 2007 Oct;30(5):482-485. [PubMed: 17803743]
  • Gramer I, Leidolf R, Doring B, Klintzsch S, Kramer E, Yalcin E, Petzinger E, Geyer J. Breed distribution of the nt230(del4) MDR1 mutation in dogs. Vet J. 2011 Jul;189(1):67-71. [PubMed: 20655253]
  • Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001 Nov; 11(8):727-33. [PubMed: 11692082]
  • Mealey KL, Meurs KM. Breed distribution of the ABCB1-1delta (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc. 2008 Sep 15;233(6):921-4. [PubMed: 18795852]
  • Mizukami K, Chang H, Yabuki A, Kawamichi T, Hossain MA, Rahman MM, Uddin MM, Yamato O. Rapid genotyping assays for the 4-base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in border collie dogs. J Vet Diagn Invest. 2012 Jan;24(1):127-34. [PubMed: 22362942]
  • Neff MW, Robertson KR, Wong AK, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC. Breed distribution and history of canine mdr1-1delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11725-30. [PubMed: 15289602]
  • Nelson OL, Carsten E, Bentjen SA, Mealey KL. Ivermectin toxicity in an Australian shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in collies. J Vet Intern Med. 2003 May-Jun;17(3):354-6. [PubMed: 12774979]