- MDR1 + HC test combination for Shepherds
- MDR1 + HC + PRA test combination for Shepherds
- MDR1 + PRA test combination for Shepherds
- PCD + MDR1 test combination for Old English Shepherd
- TNS + NCL + MDR1 NCL + TNS + MDR1 for border collie
MDR1 gene defect
A mutation in canine MDR1 gene (multidrug resistance gene) leads to a hypersensitivity to multiple drugs including Ivermectin (antiparasitic drug). Ivermectin hypersensitivity based on MDR1 gene mutation was proved in following breeds:
- Rough Collie
- Smooth Collie
- Shetland Sheepdog
- Australian Sheepdog
- Border Collie
- Longhaired whippet
- White Swiss Shepherd Dog
The highest frequency of affected animals was found in Collie breeds (up to 33 %), Australian Sheepdog (6.9 %) and Shetland Sheepdog (5.7 %).
Introduction of antiparasitic drug Ivermectin in 1980 revealed new inherited disease in several dog breeds. Ivermectin potentiates chloride ion channels in peripheral nervous system, causing lethal paralysis of some invertebrate parasites, e.g. Nematoda and Arthropoda. Ivermectin is safe for use in mammals, its target structures resides in CNS are shielded by blood-cerbrospinal fluid barrier. Main component of this barrier is P-glycoprotein, an ATP-dependent transporter of various substrates.
In P-glycoprotein defective animals, administering of ivermectin or similar drug can lead to elevated levels of drug in the CNS, resulting in potentially lethal neurotoxic reaction. These drugs include, but are not limited to: Acepromazine, Butorphanol, Doramectin, Doxorubicin, Ivermectin, Loperamide, Milbemycin, Moxidectin, Selamectin, Vinblastine, Vincristine.
Research investigating canine MDR1 as a candidate gene for ivermectin sensitivity discovered that affected dogs were homozygous for a 4-bp deletion in the fourth exon of the gene, causing a frame shift and formation of a stop codon. Resulting P-glycoprotein molecule has only about 10 % aminoacids when compared to unmutated gene product leading to complete loss of function.
MDR1 related drug hypersensitivity is inherited as an autosomal recessive trait. That means the disease affects dogs with P/P genotype only. The dogs with P/N genotype are considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.
Parent Heterozygote (P/N)
Genetic test is a fast and reliable way to reveal MDR1 gene mutation and it should precede drug therapy in predisposed breeds. The test can be performed only once in life of the animal, because the genotype does not change with age. DNA sample can be obtained from buccal swabs (non-invasive method suitable for owners) or from blood samples taken by a veterinarian.
Breeders are often confused with stating of MDR1 test results. Generally, each laboratory can use its system of result codes. Always is necessary to connect a legend explaining the result codes. Genomia lab uses for testing the same code system for all providing tests:
N = negative - searched character (such as mutation, deletion) is not present
P = positive - searched character (such as mutation, deletion) is present
In the case of MDR1 gene testing:
- N/N genotype means that the absence of 4 base pair deletion in both alleles MDR1 gene is present. Individual with this genotype (N/N) is not threatened by the emergence of neurotoxic reaction during administration of certain drugs or other substances that are substrates of P-glycoprotein. Mutation which is responsible for hypersensitivity of the drugs above, is not present in individuals with N/N genotype.
- P/P genotype means that an individual has two copies of the deleted MDR1 gene (two copies of mutation in general). Such individual is threatened by the emergence of neurotoxic reaction after administration of those drugs. Always, one copy of the gene with the 4 base deletion is inherited from one parent (mother) and the second copy of the gene with the deletion is inherited from the other parent (father).
There are some laboratories in the world that use different result codes, symbols + and -. In these cases, pay increased attention to the legend of the results. Some laboratories use the + symbol in meaning of our P (+ = mutation present), and symbol - in meaning of our N (mutation is not present).
Anyway, you may encounter with the opposite designation:
- -/- Mutated homozygote (an individual who has a mutation (deletion) in both alleles)
- +/+ For healthy individual (an individual without any mutation (deletion))
In this system, a deletion (mutation) is generally represented as a minus. The designation is based on the fact that a part of a gene (e.g. MDR1 gene) is erased (deleted). In case of MDR1 gene, 4 bases are erased. (reference: Geyer et. al.: Development of a PCR-based diagnostic test detecting a nt230 (del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Shepherd Australia)
Campbell, W. C., Fisher, M. H., Stapley, E. O., Albers-Schonberg, G. & Jacob, T. A. (1983) Science 221, 823-828.
Preston, J. M. (1983) Vet. Rec. 112, 286 (lett.).
Shan, Q., Haddrill, J. L. & Lynch, J. W. (2001) J. Biol. Chem. 276, 12556-12564.
Fisher, M. H. & Mrozik, H. (1992) Annu. Rev. Pharmacol. Toxicol. 32, 537-553.
Mealey, K.L., Bentjen, S.A., Gay, J.M. & Cantor, G.H. (2001) Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics, 11, 727-733.
Roulet, A., Puel, O., Gesta, S., Lepage, J.F., Drag, M., Soll, M., Alvinerie, M. & Pineau, T. (2003) MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. European Journal of Pharmacology, 460, 85-91.
Mealey, K.L., Northrup, N.C. & Bentjen, S.A. (2003) Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. Journal of the American Veterinary Medical Association, 223, 1453-1455,
Yas-Natan, E., Shamir, M., Kleinbart, S. & Aroch, I. (2003) Doramectin toxicity in a collie. The Veterinary Record, 153, 718-720.
Sartor, L.L., Bentjen, S.A., Trepanier, L. & Mealey, K.L. (2004) Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. Journal of Veterinary Internal Medicine, 18, 117-118.
Neff MW, Robertson KR, Wong AK, Safra N, et al. Breed distribution and history of canine mdr1-1∆, a pharmacogenetic station that marks the emergence of breed from the collie lineage 2004. PNAS 101:11725-11730.
Geyer J, Döring B, Godoy JR, Moritz A, Petzinger E. 2005. Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Australian Shepherd. J Vet Pharmacol Therap 28:95-99.
Result report preview
Breed list - total 11 different breeds. Show list of all breeds Hide breeds
- Australian Shepherd
- Border Collie
- Collie Rough
- Collie Smooth
- Longhaired Whippet
- Miniature American Shepherd
- Miniature Australian Shepherd
- Old English Sheepdog (Bobtail)
- Shetland Sheepdog
- Toy Australian Shepherd
- White Swiss Shepherd Dog