Canine Disease Profile – Multi-Drug Resistance (MDR1)
Written by Dr. David W. Silversides, DVM.
Multi-Drug Resistance (MDR1) is a genetic condition wherein dogs that carry mutations in the ABCB1 gene (also called MDR1 gene) are hyper-sensitive to commonly used veterinary drugs; for this reason, it is considered a “pharmacologic” genetic disease.
The MDR1 gene codes for a transporter protein that protects the brain from toxic small molecules by binding and transporting the molecules out of the brain. A dog with two mutated copies of the MDR1 gene and thus no functional transporter protein is particularly sensitive to toxicity from a range of common drugs used in veterinary medicine including antiparasitic drugs (macrocyclic lactones such as Ivermectin), antibiotics (such as Erythromycin), tranquilizers (such as Acepromazine), antidiarrheal drugs (such as Loperamide), opioids (such as Butorphanol), and other drugs including cancer chemotherapy drugs (such as Vincristine, Vinblastine, Doxorubicin).
Clinical Signs of MDR1
Signs of toxicity can include loss of alertness, excessive salivation, pupil dilation, tremors, ataxia, seizures, slowed heart rate, coma, respiratory arrest and death. Note that signs of toxicity are much more severe for the animal that is double mutant but have been reported for animals that carry a single mutation. For this reason, the heredity of Multi-Drug Resistance is considered as dominant with variable penetrance, and although the double mutant (M/M) animal is most at risk of showing severe toxicity to medications, care should still be taken when giving medication to carrier (M/N) animals.
MDR1 and the Shepherd Breeds
The mutation for MDR1 is found in a number of dog breeds, mostly of the Shepherd and Collie-type or their crosses. These breeds include:
Australian Cattle Dog, Australian Shepherd, Berger Picard, Border Collie, Chinook, Collie, German Shepherd, Long-Haired Whippet, McNab Shepherd, Miniature American Shepherd, Miniature Australian Shepherd, Old English Sheepdog, Rough Collie, Ryukyu Inu, Shetland Sheepdog, Shiloh Shepherd, Silken Windhound, Smooth Collie, Waller, White Swiss Shepherd.
This list of breeds indicates that the mutation that is the cause of the problem is fairly old, and happened before the Shepherd-type breeds were segregated into their present form.
Medication Intolerence
The mutation that is the cause of MDR1 is a deletion of four bases within the ABCB1 gene. In order for toxicity to occur, dogs have to be given a pharmacological product. Dogs that are clear (N/N) for the mutation will have normal, wild-type tolerance to medications. Dogs that have one normal and one mutated copy of the mutation (M/N) are felt to have somewhat reduced tolerance (i.e. somewhat increased toxicity) to medications.
The real clinical problem and the animal to avoid giving medication to is the double mutant (M/M) animal, for which otherwise safe doses of medication become highly toxic. The mutation was reported in 2001, so breeders and veterinarians have had access to DNA tests to identify carriers and animals at risk for almost twenty years. Despite this fact, M/N and M/M animals are still being identified.
DNA Sequencing Profiles and Frequencies
Here are representative DNA sequencing profiles and mutation frequencies that we have seen:
For additional genetic information and references regarding Multi-Drug Resistance (MDR1) in dogs, please refer to the following link: https://labgenvet.ca/en/disease/multi-drug-resistance-mdr1-gene-abcb1/.
A comprehensive list of simple genetic diseases in dogs can be found at: https://labgenvet.ca/en/dog-genetic-disease-search/.
© 2018 David W. Silversides