A dog with the MDR1 gene mutation, also known as multidrug sensitivity, is susceptible to neurological toxicosis and life-threatening reactions if certain drugs are administered (Mealey and Meurs, 2008). This condition is caused by the deletion of 4-base pairs of the MDR1 gene (Suriyaphol, 2011). P-glycoprotein (P-gp) is a product of this gene and a well-known multidrug transporter in the adenosine triphosphate binding cassette family (Ahmed Juvale et al, 2022). P-gp is found in various tissues throughout the body, including at the physiological barriers such as the blood-brain barrier where it acts as a drug-efflux pump (Geyer et al, 2009). Under normal conditions, the role of P-gp is protective. This includes the distribution and excretion of several drugs and restricting access of certain drugs and xenobiotics through the Blood-brain barrier (Gramer et al, 2011). P-gp function is impaired in dogs with a mutation of the MDR1 gene. This causes susceptibility to neurotoxicity if P-gp substrates and xenobiotics accumulate and cross the Blood-brain barrier, subsequently penetrating the central nervous system (Geyer et al, 2009).
Mutation of the MDR1 gene is an inherited condition most frequently observed in herding breeds such as the Collie, Australian Shepherd and Shetland Sheepdog (Mealey et al, 2023). Many of the drugs known to be dangerous if administered to a dog with the MDR1 mutation are frequently used in clinical practice, including acepromazine, butorphanol, ivermectin and milbemycin oxime (Connors, 2017). It is therefore essential that veterinary professionals are aware of this condition, particularly when working with the high-risk breeds, so that they can assess the risks, administer the safest drugs and provide accurate advice to owners.
Inheriting the MDR1 gene mutation
An overview of genotype possibilities is included in Table 1. In summary, these are homozygous normal (unaffected), heterozygous or homozygous mutations (affected). Offspring can inherit this gene if their parents are either homozygous or heterozygous for the mutation. Dogs only need to inherit one of the mutated genes to be at risk if certain drugs are administered. There is a 50% chance that heterozygous dogs will pass on the mutation to their offspring. These dogs are classed as normal/mutant and are at risk of adverse drug reactions. If a dog inherits two copies of the mutated gene, they are referred to as homozygous for that gene (Mealey, 2016) and are classed as mutant/mutant. Affected dogs will always pass on one copy of the mutated gene to their offspring (Suriyaphol, 2011). Homozygous dogs (mutant/mutant) are extremely susceptible to adverse and life-threatening reactions when administered certain drugs (Barroso et al, 2022).
Table 1. Expected inheritance of the MDR1 gene
| Sire | |||
|---|---|---|---|
| Dam | Normal/normal | Normal/mutant | Mutant/mutant |
| Normal/normal | Normal/normal | Normal/normalNormal/mutant | Normal/mutant |
| Normal/mutant | Normal/normalNormal/mutant | Any combination possible | Normal/mutantMutant/mutant |
| Mutant/mutant | Normal/mutant | Normal/mutantMutant/mutant | Mutant/mutant |
☐= homozygous (normal gene)
☐= heterozygous
☐= homozygous (mutated gene)
Sources: Suriyaphol (2011); Mealey (2016); Connors (2017); AffinityDNA (2024); EasyDNA (2024); Gribbles Veterinary Pathology (2024)Dangerous drugs
Several drugs are known to cause neurological toxicity in dogs with the MDR1 gene mutation (Table 2). According to Mealey et al (2023), the recommended dose reduction of P-gp substrates in dogs with the mutation is 25% in heterozygous cases (normal/mutant) and 50% in homozygous cases (mutant/mutant). Drugs known to cause sensitivity are prescription-only drugs (POM-V), thus the decision to prescribe a particular drug is the responsibility of the veterinary surgeon. A table of high-risk breeds and dangerous drugs could be displayed in practice to provide a visual guide to veterinary professionals and owners.
Table 2. Drugs known to cause sensitivity in dogs with the MDR1 gene mutation
| Drug category | Active ingredient |
|---|---|
| Antibiotic |
|
| Antiparasitic |
|
| Antineoplastic |
|
| Gastroenterological |
|
| Other |
|
Affected breeds
In the early 1980s, a new parasiticide product containing ivermectin was released onto the veterinary market. This potent drug belongs to the macrocyclic lactone family and has broad spectrum properties (Vercruysse and Claerebout, 2014) making it an ideal parasiticide for use in domestic dogs, domestic cats (Felis catus) and other species. Ivermectin and several other drugs are P-gp substrates and use the P-gp transporter system for several activities. Evidence of sensitivity to ivermectin was originally discovered in the 1980s, particularly in the collie breed. A clinical study by Paul et al (1987) found that when oral ivermectin was administered in collies it produced neurological toxicosis to varying degrees. A total of 14 dogs were administered a 0.4% solution of oral ivermectin at 100 μg/kg followed by 200 μg/kg after a 1-month wash-out period. Mild neurological signs were observed in three dogs administered 100 μg/kg (disorientation, confusion, mild ataxia) and severe signs were subsequently observed in 7 dogs administered the higher dose (disorientation, confusion, ataxia, ptyalism, emesis, tremors, depression, non-responsiveness, stupor, coma). A third dose of 600 μg/kg was administered one month later to seven dogs that did not develop severe signs following the 200 μg/kg dose. Interestingly, none of these dogs experienced severe neurological signs and only three dogs showed mild signs (ptyalism, disorientation). Finally, a dose of 2500 μg/kg was administered after another one-month wash-out period to seven dogs that did not develop severe signs following the 200 μg/kg and 600 μg/kg doses and only 1 dog experienced severe neurological signs (emesis, ptyalism, ataxia, tremors, weakness, severe depression, total unresponsiveness, recumbency) and five dogs experienced mild signs (ptyalism, ataxia, confusion, poor responsiveness). Although all dogs survived, those with severe neurological toxicosis required supportive care while comatose. The results of this study highlighted the range of susceptibility to ivermectin in the collie breed.
This study was conducted before the discovery of the herding breed predisposition to the MDR1 gene mutation in 2001 (Mealey et al, 2001). The MDR1 genotype of each dog may explain the range of sensitivities. Dogs that developed severe neurological signs at doses of 100 μg/kg and 200 μg/kg may have been heterozygous or homozygous for the mutated gene and therefore at an increased risk of adverse drug reactions. In contrast, dogs that did not experience mild or severe clinical signs, even at the higher doses (600 μg/kg and 2500 μg/kg), may not have had the MDR1 gene mutation. Several other studies have documented the frequency and severity of neurological toxicosis in the collie, highlighting the increased risk of ivermectin sensitivity in this breed (Easby 1984; Pulliam et al, 1985; Heit et al, 1989; Smith et al, 1990; Mealey et al, 2001). As there are many other P-gp substrates, it is possible that dogs with the mutation would experience differing levels of drug sensitivity in contrast to their sensitivity to ivermectin (Mealey et al, 2001).
A clinical study involving 642 dogs in the UK identified several herding breeds with the MDR1 gene mutation including the rough collie, smooth collie, Australian shepherd, Shetland sheepdog, old English sheepdog and the border collie (Tappin et al, 2012). The mutation was not identified in 34 other breeds (n=449 dogs). Homozygous cases (mutant/mutant) were identified in 52% of the rough collies (n=12), 45% of the smooth collies (n=5) and 12% of the Shetland sheepdogs (n=6). Heterozygous cases (normal/mutant) were highest in the smooth collie (55%, n=6) and Shetland sheepdog (47%, n=23).
A clinical study in Italy identified the MDR1 gene mutation in 88% of rough collies (n=168/190), with 44% (n=83) identified as homozygous (mutant/mutant) and 45% (n=85) identified as heterozygous (Marelli et al, 2020). According to Mealey et al (2023) the estimated frequency of the MDR1 gene mutation in the collie is 70%. This figure is consistent with the findings of Tappin et al (2012) and Marelli et al (2020), highlighting the prevalent and familiar occurrence of this mutation in the collie. Several other breeds of the collie lineage are known to be sensitive to ivermectin and other P-gp substrates, including some non-herding and mixed breeds. This includes the English shepherd, McNab shepherd, German shepherd, white Swiss shepherd, Wäller, long-haired whippet, silken windhound and some mixed breeds, including those of the collie lineage (Neff et al, 2004; Tappin et al, 2012; Beckers et al, 2022; Marelli et al, 2020).
Clinical signs of toxicity
The onset and severity of neurotoxic signs depend on the administered dose (Geyer and Janko, 2012) and whether the dog is heterozygous or homozygous for the mutated gene (Mealey, 2016). Heterozygous dogs may be asymptomatic (Mealey et al, 2001) or milder signs may be observed in contrast to dogs that are homozygous for the mutation (Mealey, 2016). There are a range of signs of toxicity from mild to severe which may include agitation, panting, disorientation, weakness, mydriasis, ataxia, depression, tremor, emesis, uncoordinated movement, ptyalism, respiratory compromise, blindness, recumbency, stupor, seizure, coma and death (Paul et al, 1987; Geyer and Janko, 2012; Gaens et al, 2019; Boatright, 2024).
Genetic testing for the MDR1 gene
Obtaining a DNA sample for genetic testing is relatively straightforward and can be conducted by the student or registered veterinary nurse. Testing can be conducted using whole blood or through buccal swab sampling (Baars et al, 2008). Buccal swab sampling can be conducted by the owner at home without the need for assistance from a veterinary professional (Figure 1a). Samples are often sent to an external laboratory for testing involving the use of polymerase chain reaction (Geyer et al, 2005), which is a rapid and robust process by which to determine the MDR1 genotype of a dog. This will assist owners and veterinary professionals in understanding the risk of multidrug sensitivity. Reporting of results may vary depending on the laboratory conducting the test. Generally, there are three possible outcomes: homozygous (normal/normal), heterozygous (normal/mutant) or homozygous (mutant/mutant) (Connors, 2017; AffinityDNA, 2024; EasyDNA, 2024; Gribbles Veterinary Pathology, 2024) (Table 1). DNA testing conducted directly via an external laboratory costs between £48.00 (Laboklin, 2023) and £55.00 (AffinityDNA, 2024; EasyDNA, 2024), making it affordable for many dog owners.
General management of high-risk dogs in practice and at home
Where there is a risk or the dog is confirmed to have the mutation, appropriate signage on the patient's kennel is advised to inform clinical staff of the risk to the patient. Signage could be used in multiple scenarios, for example, when accommodating a high-risk breed that has not been tested for the mutation (Figure 1b). Additionally, signage could be used when accommodating patients confirmed to have the MDR1 gene mutation (Figure 1c). This provides a visual reminder to ensure appropriate risk management strategies are adopted. Clinical staff communicating with the owner should ask whether their dog has been tested for the mutation and update records accordingly. It is imperative that the patient's record is kept up to date, particularly in cases where histories are sent to other practices in the event of the owner changing practice. If a dog is confirmed to have the MDR1 gene mutation, this information can also be included when registering or updating its microchip details.
Owners of any breed can opt for genetic testing, but it should be recommended to owners of high-risk breeds to identify the risk of multidrug sensitivity. This can be recommended during consultation, especially during obstetric or new puppy consultations. It can be explained that obtaining a DNA sample for genetic testing is relatively straightforward, and that results can be used by veterinary professionals to understand whether certain drugs can be administered or if they should be avoided because of the risk of adverse reactions. As some drugs may result in severe adverse reactions, it may be unsafe to administer them unless the dose is markedly reduced (Mealey and Fidel, 2015). Alternative drugs should be considered in some cases where there is a significant risk. Dogs that have been administered any of the drugs listed in Table 2 should be closely monitored for signs of neurological toxicity and owners should also be advised to monitor when administering at home.
Active ingredients such as abamectin are contained in some environmental pesticides and are known to cause neurological toxicosis in dogs with the MDR1 gene mutation (Mealey, 2016). Exposure to these products should be prevented for all dogs to ensure safety. Furthermore, exposure to ivermectin can occur via multiple routes, including primary ingestion of the ingredient and secondary ingestion by eating the faeces from an animal treated with ivermectin (Bates, 2020). For this reason, dogs with the MDR1 gene mutation should not be exposed to animal faeces, especially if they exhibit repeated coprophagic behaviour. They should also be prevented from grooming another animal that has been treated with topical ivermectin or other potentially dangerous drugs.
Owners of susceptible breeds should be encouraged to purchase drugs from their veterinary practice, as opposed to online, to ensure that they give the animal the safest product and dose.
Conclusions
While severe and life-threatening drug reactions can occur in dogs with the mutation, the risk of this can be reduced by knowing a dog's MDR1 genotype. Dogs with the mutation can be easily managed by limiting their exposure to certain drugs. Attempts could be made to eliminate the mutated gene through careful breeding; however, this could potentially lead to a depletion of breeding stock, particularly in some of the vulnerable breeds. For this reason, removing dogs with the mutation from a breeding programme is not recommended. A simple test via blood or buccal swab sampling will provide the owner and veterinary professional with the information. In cases of neurological toxicity, clinical signs vary depending on whether dogs are heterozygous or homozygous for the mutated gene. Many of the drugs known to be dangerous are used in everyday clinical practice. Knowledge of this condition will assist the veterinary professional with safe drug dosage, administration and management, thus promoting patient safety.
KEY POINTS
- The MDR1 gene mutation is an inherited condition most frequently observed in herding breeds such as the collie, Australian shepherd and Shetland sheepdog.
- There is a risk of neurological toxicity in any dog with the mutation, but it is greater in dogs that are homozygous for this gene.
- Some drugs known to be dangerous in dogs with the mutation are frequently used in clinical practice, for example, acepromazine, butorphanol, ivermectin and milbemycin oxime.
- The recommended dose reduction of P-gp substrates in dogs with the mutation is 25% in heterozygous cases (normal/mutant) and 50% in homozygous cases (mutant/mutant).
- Obtaining a DNA sample for testing is straightforward and can be conducted by the student veterinary nurse or registered veterinary nurse, or at home by the owner (buccal swab sampling).