MDR1 Gene Mutation in Dogs and Cats

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MDR1 Gene Mutation | Dr. Jean Dodds

The MDR1 Gene Mutation is fairly easy to understand. However, many of the descriptive scientific labels may seem quite complex, so we shall simplify them here.

  • Polypeptide – Linear polymer of many amino-acids bonded together in a chain, forming part of (or the whole of) a protein molecule.
  • Glycoprotein – Any proteins that have carbohydrate groups attached to the polypeptide chain.
  • Permeability Glycoprotein 1 (P-glycoprotein) – A drug transporter protein that plays a role in the absorption, distribution, metabolism, and excretion of drugs via the bile and urine. Its physiological role is the protection of cells in the central nervous system (CNS) from toxic substances or metabolites, which serves to limit drug absorption and distribution. Defective P-glycoprotein function can lead to severe, potentially fatal, adverse drug reactions because of enhanced CNS exposure to drugs (from lack of functional P-glycoprotein at the blood-brain barrier) and/or enhanced systemic exposure to drugs (from lack of P-glycoprotein-mediated biliary and/or renal drug excretion).
  • Multiple Drug Resistant 1 Gene (MDR1) – The gene that encodes the P-glycoprotein to do its job of limiting entry of toxic substances into the CNS.

As stated by Dr. Katrina Mealy of Washington State University Veterinary Clinical Pharmacology Laboratory (WSU VCPL) , “Defective P-glycoprotein function can occur in dogs and cats with MDR1 gene mutations but can also result from drug-drug interactions. Several commonly used drugs can inhibit P-glycoprotein function, even in animals with normal MDR1 gene structure. Consequently, veterinarians may encounter dogs and cats with intrinsic (genetically mediated) P-glycoprotein dysfunction, as well as with extrinsic, or acquired, P-glycoprotein dysfunction (animals receiving a drug that inhibits P-glycoprotein function)”.

If the MDR1 gene undergoes one or more mutations, it can allow a higher absorption of drugs and toxic substances to enter the CNS which then can breach the blood-brain barrier and create adverse reactions.

Heritable MDR1 gene mutations can affect any dog or cat breed and breed crosses and mixed breeds , but are most commonly found in dog breeds of herding breed ancestry such as the Collie, Long-haired Whippet, Australian Shepherd, Miniature Australian Shepherd, McNab Shepherd, and Silken Windhound. In fact, up to 70% of Collies have the mutated gene, whereas the other commonly affected breeds listed here have MDR1 gene frequencies in descending order of 65-30%. Shetland sheep dogs have this mutation with a 15% estimated frequency. Perhaps surprisingly, the frequency of this gene mutation in Border Collies is low (< 5%).

Fortunately, the WSU VCPL has developed and offers a blood and a cheek swab test to detect the MDR1 mutation. All breeders and caregivers of affected breeds should be encouraged to have this testing done. The test costs less than $100. Compared to the potentially fatal adverse drug reactions these mutations can cause, it is well worth the price.

Does this mean that dogs and cats with the MDR1 gene mutation cannot have any drugs? No; the scientific community has identified many drugs that can and cannot be given to MDR1 affected companion pets. Confounding issues exist, though, that can add to the confusion surrounding this testing:

  1. Dosage level of drug
  2. Drug interactions that may heighten or otherwise alter P-glycoprotein dysfunction
  3. Genes involved
Sample Drugs that cause P-Glycoprotein Dysfunction
  • Loperamide (Imodium; antidiarrheal agent) – Complete avoidance recommended
  • Acepromazine (tranquilizer and pre-anesthetic agent) – Reduce the dose
  • Butorphanol (analgesic and pre-anesthetic agent) – Reduce the dose
  • Chemotherapy agents (vincristine, vinblastine, doxorubicin, paclitaxel, vinorelbine) – Reduce the dose
  • Doramectin (antiparasitic)
  • Erythromycin (antibiotic)

FDA-approved antiparasitic drugs such as ivermectin (Heartgard), selamectin (Revolution), milbemycin oxime (Interceptor) and moxidectin (Advantage Multi) have been tested and found safe for MDR1-affected dogs when given at the prophylactic heartworm preventative dosage level. Higher doses are often prescribed for mange or other conditions and can cause adverse reactions.

If the antiparasitic drug is given with a spinosad (Comfortis; Tri-Fexis), afoxolaner (NexGard), fluralaner (Bravecto) or related flea preventatives, or ketoconazole, itraconazole, fluconazole or related antifungals, then serious drug-drug interactions can
occur. It is best to avoid these combinations altogether. Further, these flea preventives are contraindicated for dogs prone to seizure disorders.

Metronidazole is a drug known to cause neurological toxicity and incoordination. But, P-glycoprotein does not transport metronidazole. Metronidazole toxicity, instead, typically results from using it at an increased dose and and/or long duration, and is independent of the MDR1 mutation.

Genetics

Simply knowing if a companion pet has a MDR1 gene mutation is not enough. We need to know if it is present in the homozygous or heterozygous form for both treatment and breeding purposes.

MDR1 Gene Homozygous = mutant/mutant. Affected animals have 2 copies of the mutant allele and always pass 1 copy of the defective gene to their offspring. Homozygotes are more likely to have severe (life-threatening) adverse drug reactions.

MDR1 Gene Heterozygous = mutant/normal. Affected animals have 1 copy of the mutant allele and 1 copy of the normal allele and have a 50% chance of passing the defective gene to their offspring. Heterozygotes tend to have less severe adverse drug reactions.

The ideal situation would to breed only normal/normal dogs and cats. Then again, the MDR1 gene mutation prevalence is so high in some dog breeds that eliminating them from the gene pool likely would entail inbreeding and linebreeding with a resulting rise in prevalence of other heritable conditions such as the autoimmune and other diseases (hypothyroidism and thyroiditis, inflammatory bowel disease, hemolytic anemia and thrombocytopenia, systemic lupus erythematosus, glomerulonephritis, chronic hepatitis, hip and elbow dysplasia, dermatomyositis, cataracts and keratoconjunctivitis sicca). Therefore, sometimes we need to breed a MDR1 gene heterozygous normal/mutant dog to
maintain a large enough gene pool. Dogs and cats that are homozygous mutant/mutant for the MDR1 gene should not be used for breeding, as basically they will pass along the MDR1 mutation to all their offspring.

As stated above with respect to MDR1 gene mutations, homozygotes have no P-glycoprotein function, whereas heterozygotes have partial function. So, homozygotes are more likely to have severe life-threatening drug reactions, whereas heterozygotes tend to have less severe drug reactions.

My advice: Get your companion animal tested for the MDR1 gene mutation; particularly if you have a highly affected breed. If your companion pet proves positive for the condition, please find a veterinarian who is up-to-date on the potential drug toxicity issues and can offer sound advice.

W. Jean Dodds, DVM
Hemopet / NutriScan
11561 Salinaz Avenue
Garden Grove, CA 92843

References

Mealey, Katrina. “MDR1 Gene Mutations & Drug Therapy.” Clinician’s Brief, May 2016. Web. 26 Mar. 2017. http://www.cliniciansbrief.com/article/mdr1-gene-mutations-drug-therapy.

“Multidrug Sensitivity in Dogs.” VCPL – MDR1 Test. Veterinary Clinical Pharmacology Laboratory, n.d. Web. 26 Mar. 2017. https://vcpl.vetmed.wsu.edu/.

 

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