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Multidrug Resistance Gene: mdr1 mutation (Ivermectin Sensitivity)

This test is offered by the Animal Health Trust under licence from Washington State University, Pullman, WA, USA. Please note that under the terms of this licence we can only accept samples from addresses within the United Kingdom.

This mutation (mdr1-1Δ) causes sensitivity to the anti-parasitic agent ivermectin and a number of other drugs. The mutation lies in the gene for P-glycoprotein, which is involved in transporting drugs across the blood-brain barrier, and allows build up of drugs in the brain causing potentially fatal neurotoxicity. P-glycoprotein mediated biliary excretion is also inhibited (delaying clearance and therefore enhancing toxicity of P-glycoprotein substrate drugs beyond simple CNS toxicity). The condition has been found in the following breeds: Rough Collie, Border Collie, Australian Shepherd, Miniature Australian Shepherd, Old English Sheepdog, Shetland Sheepdog, German Shepherd, English Shepherd and McNab Shepherds.

Results

Breeders using the test will be sent results identifying their dog as belonging to one of three categories:

This dog is CLEAR of the Multi-Drug Resistance (mdr1) mutation: These dogs have two normal copies of DNA. Clear dogs will not show drug sensitivity as a result of the mdr1 mutation, although we cannot exclude the possibility that they could show drug sensitivity due to other mutations they might carry that are not detected by this test.

This dog has ONE COPY of the Multi-Drug Resistance (mdr1) mutation: These dogs have one copy of the mdr1 mutation and one normal copy of DNA. These dogs may show some drug sensitivity as a result of the mdr1 mutation and will pass the mutation on to approximately 50% of their offspring. We cannot exclude the possibility that carriers might also show drug sensitivity due to other mutations they might carry that are not detected by this test.

This dog has TWO COPIES of the Multi-Drug Resistance (mdr1) mutation: These dogs have two copies of the mdr1 mutation and will show drug sensitivity.

Breeding

Breeding from parents with and without the mdr1 mutation will produce the following combinations of pups:

Parents	Litters 1
clear x clear	all clear
clear x one copy of mdr1	approximately 50% clear, 50% one copy of mdr1
clear x two copies of mdr1	all one copy of mdr1
one copy of mdr1 x one copy of mdr1	approximately 25% clear, 50% one copy of mdr1, 25% two copies of mdr1
one copy of mdr1 x two copies of mdr1	approximately 50% one copy of mdr1, 50% two copies of mdr1
two copies of mdr1 x two copies of mdr1	all two copies of mdr1

 

1The percentages shown here are for guidance only and apply when a statistically-significant number of pups is considered.

Mealey,K.L, Bentjen,S.A, Gay,J.M. and Cantor,G.H. (2001) Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11 727-733

Neff,M.W, Robertson,K.R., Wong,A.K., Safra,N., Broman,K.W., Slatkin,M., Mealey,K.L. and Pederson,N.C. (2004) Breed distribution and history of canine mdr1 1Δ, a pharmacogenetic mutation that marks emergence of breeds from the collie lineage. Proc Natl Acad Sci 101 11725-11730

Mealey,K.L., Fidel,J., Gay,J.M., Impellizeri,J.A., Clifford,C.A. and Bergman,P.J. (2008) ABCB1-1D Polymorphism Can Predict Hematologic Toxicity in Dogs Treated with Vincristine. J Vet Intern Med 22:996–1000

Coelho, J. C., Tucker, R., Mattoon, J., Roberts, G., Waiting, D. K., Mealey, K. L. (2009) Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1D mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency. J. vet. Pharmacol. Therap. 32 417–421