Multi-drug resistance gene (MDR1) in dogs

The problem associated with the Multi-drug resistance gene (MDR1) mutation first became apparent when it was noticed that ivermectin administration lead to severe neurological signs, seizures and death in Rough Collies. The gene defect affects many herding breeds and means that these breeds can be particularly sensitive to certain drugs.

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The MDR (multi-drug resistance) gene contains the code for instructions to make special pumps in cells. These pumps move toxins from the inside of cells to the outside (particularly important in the brain) and help remove them from the body. This prevents the build-up of potentially harmful drugs and toxins within the body. If this gene is damaged or mutated the pumps do not work properly causing serious complications. A mutation of this gene was first found in Rough Collies but has since been identified in several related herding breeds and their crosses.

In some dogs an abnormal form of this gene is present and the cell pumps in these animals do not work properly. All genes occur in pairs in the body and if only one gene in the MDR gene pair is affected then there is a reduction in function of the pumps. However, if both genes are abnormal then the affected animal can be extremely sensitive to the toxic effects of some drugs. Many of the drugs removed by these pumps are commonly used in veterinary practice: such as sedatives or pre-medications used before surgery; chemotherapy agents; drugs for treating parasites (heartworm and Demodex spp); for heart conditions and in many other circumstances.

Almost all the breeds found to carry the MDR1 mutation are herding breeds, but the mutation is far more common in some populations than others. Almost three-quarters of Rough Collies and nearly a half of Australian shepherds in the UK are affected. In the UK around one in three Shelties, five in a hundred Old English Sheepdogs and two in a hundred Border collies carry the mutated gene. In the US the mutation is seen in half of all Rough Collies and is common in Long-haired Whippets and Australian Shepherds (with around one-third being affected). Other breeds affected in the US include McNab, Silken Windhound, English and German shepherds, Border Collie, and Old English Sheepdogs.

If your dog has been unlucky enough to have a severe reaction to one of the drugs affected by the gene mutation, then you may already know that it has a problem.

Some drugs such as ivermectin and imodium can build up in the brain if the gene mutation is present. This can cause signs such as anorexia, drooling, tremors, blindness, coma or even death.

Dogs may be sedated with acepromazine or butorphanol for surgery and those with the defective gene remain sedated for a long period. There are rare reports of the antibiotic erythromycin causing neurological signs in Rough Collies, so this drug may be best avoided in dogs with the MDR1 mutation, particularly if alternative drugs are an option.

Selamectin, milbemycin and moxidectin are used to treat parasite infections in dogs but have caused neurological signs at high doses in the dogs with MDR1 gene mutation. These drugs are safe to use at heartworm prevention doses in dogs with the MDR mutation provided the manufacturers’ recommendations are followed. Some drugs used in the treatment of cancer may have increased side-effects in dogs carrying the gene mutation.

There is a screening test for the abnormal gene. This requires the collection of a blood sample or a mouth swab which can be done at any age. This test can be run routinely and should always be done before breeding from a dog in one of the ‘at risk’ breeds. The test is part of the Official UK KC DNA Testing Scheme in Australian shepherd, Border Collie, Rough Collie, Sheltie and Smooth Collie and can tell whether the dog has one or two abnormal genes.

Animals with the MDR1 defect live perfectly normal lives until they are exposed to one of the important drugs. If your pet has a MDR1 mutation make sure your veterinarian is aware of this and remind them every time your pet has treatment. Also make sure that anyone else looking after your pet such as boarding kennels and dog sitter or walkers is also aware. This will reduce the risk of your pet accidentally being given a medication that they may be sensitive to.

The MDR-1 mutation is passed on to the puppies of any affected dog. If the puppy receives a mutated gene from a parent they will be affected, even if they receive a normal gene from their other parent as well. It is therefore important to know whether dogs are carrying this gene before they are allowed to breed.

In an ideal world we would only allow dogs with normal MDR1 genes to produce puppies. Sadly, the MDR1 gene is present in such a large percentage of Rough Collies and Australian Shepherds, that breeding from only dogs with normal genes would limit the pool of breeding dogs too much. For this reason, it may be necessary to breed from dogs that have only one abnormal gene knowing that around half of their puppies will be affected.