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Canine Mendelian disease record

MDR1 (Multidrug Resistance 1) Medication Sensitivity

MDR1 (Multidrug Resistance 1) Medication Sensitivity. Autosomal dominant. Observed in 30 of 266 breeds tested in the Sniff Atlas, with measured at-risk genotype frequencies drawn from 242,642 dogs (Donner 2023). Because this is a dominant trait, a single copy places a dog at risk rather than making it a silent carrier; whether the phenotype appears still depends on penetrance, modifier genes, and environment.

Dominant trait. A single copy of this variant places a dog at risk; it does not make the dog a silent carrier. The breed frequencies below are therefore at-risk frequencies, and penetrance plus modifier genes determine whether the phenotype actually appears.

OMIA identifier
OMIA:001402-9615
Autosomal dominant
Source dataset
Sniff Atlas v1.0.1 / DOI
About this disease

From OMIA's curated record

Documented in OMIA (Online Mendelian Inheritance in Animals). This describes the disease as recorded in the published literature, not a prediction for any individual dog. As of 2026-06-03.

Summary

Multidrug resistance 1 is caused by a lack of P-glycoprotein drug transporter in the blood-brain barrier, which is characterized by neurotoxicity after administration of certain drugs.

Clinical features

In the 1980s, dogs of predominantly herding breeds were reported with adverse effects following drug administration. When these dogs are administered xenobiotics at an appropriate dose, the drug accumulates in the brain leading to severe neurotoxicity. Affected animals may present with generalised tremor, agitation, severe panting, hypersalivation, lethargy, disorientation, depression, mydriasis, loss of menace, loss of papillary light responses, blindness, seizures, proprioceptive ataxia, weakness, bradycardia, obtundation, recumbency and coma (Mealey et al., 2001; Bissonnette et al., 2009; Gaens et al., 2019). Mydriasis is suggested to be the most sensitive sign (Bissonnette et al., 2009). [IT thanks DVM student Hannah Edgell for contributions to this entry in April 2022]

Molecular genetics

By cloning and sequencing a very likely candidate gene (based on knowledge of the biochemistry and physiology of the disorder) Mealey et al. (2001) identified the causative mutation as a 4 bp deletion (c.296_299del4; omia.variant:469) in the ABCB1 (MDR1) gene, which encodes P-glycoprotein drug transporter (P-gp). The deletion causes a frame shift, introducing several stop codons, which cause premature protein truncation. P-gp is an ATP-driven drug transporter that binds a variety of drugs in the endothelial cells and transports them back into the blood, preventing them from diffusing into the brain. P-gp is expressed in brain capillaries, renal proximal tubules, liver, small bowel, colon, placenta, and brain endothelium. P-gp is also expressed at high levels in tumor cells, allowing them to resist a spectrum of chemotherapeutic drugs (Mealey et al., 2001, Gramer et al., 2011). Han et al. (2010) reported a different causal mutation, c.73insAAT (omia.variant:607), in an ivermectin-sensitive Border Collie. However, this allele is reflected by the reference sequence CanFam3.1. Alves et al. (2011) reported a base substitution (c.-6-180T>G, (omia.variant:442) in intron 1 that "was significantly more frequent in epileptic [Border Collies] resistant to [phenobarbital] treatment than in epileptic BCs responsive to PB treatment". However, in a "multicentre retrospective, case-control study", Gagliardo et al. (2019) showed that there is no association between the likely causal variant c.-6-180T>G [omia.variant:442] and refractory epilepsy in a "multi-breed cohort of dogs".

Pathology

P-glycoprotein (P-gp) is an adenosine triphosphate driven drug transporter, encoded for by the ABCB1 gene. P-gp normally transports some chemotherapeutic agents (Vinca alkaloids, doxorubicin), immunosuppressants (cyclosporine, tacrolimus), macrocyclic lactone antiparasitic drugs (ivermectin, loperamide, milbemycin, selamectin, moxidectin), HIV-1 protease inhibitors, and steroid hormones. It is expressed in many tissues, including the liver, kidneys, and intestines, where it functions to reduce drug uptake from the gut and promote drug excretion in the bile duct and urine (Gramer et al., 2011). Moreover, it is a major component of the blood-brain barrier, thus is crucial in protecting the central nervous system from exposure to certain drugs (Schinkel et al., 1996). Dogs that are homozygous for causal ABCB1 mutations lack P-gp, and consequently are susceptible for certain drugs to penetrate into the brain, and accumulation of high drug levels in the brain leads to toxicity (Mealey, 2008). [IT thanks DVM student Hannah Edgell for contributions to this entry in April 2022]

Prevalence

In the USA, the frequency of the 4bp deletion allele [omia.variant:469] was reported as 56-75% in collies, 7% in Shetland sheepdogs, 29% in Australian shepherds, 1% in Border collies, 1% in old English sheepdogs, 20% in miniature Australian shepherds, 29% in longhaired whippets, 16% in silken windhounds, and 6% in German shepherds (Mealey and Meurs, 2008, Mealey, 2008). In Germany, the frequency of the same allele was reported as 59% in collies, 45% in longhaired whippets, 30% in Shetland sheepdogs, 24% in miniature Australian shepherds, 22% in Australian shepherds, 17% in Wällers, 14% in white Swiss shepherds, 4% in old English sheepdogs, 1% in Border collies, 8% in herding breed mixes, and 2% in mixed breeds (Gramer et al., 2011). Mizukami et al. (2013) developed a PCR-RFLP genotyping test for the c.-6-180T>G mutation [omia.variant:442], and in 472 Border Collies in Japan "demonstrated the frequencies of the T/T wild type, T/G heterozygote, and G/G mutant homozygote to be 60.0%, 30.3%, and 9.8%, respectively, indicating that the frequency of the mutant G allele is extremely high (24.9%) in Border Collies. The results suggest that this high mutation frequency of the mutation is likely to cause a high prevalence of phenobarbital-resistant epilepsy in Border Collies." Mizukami et al. (2016) reported the frequency of the 4bp deletion allele [omia.variant:469] as 0.002 in 500 Border collies in Japan. Lerdkrai et al. (2021) "clarified the prevalence of MDR1 nt230(del4) [omia.variant:469] in 263 dogs of eight purebred dog breeds in Thailand ... . Rough Collies, Australian Shepherds, Shetland Sheepdogs, and Old English Sheepdogs were affected by the mutation with mutant allelic frequencies of 57.14%, 12.82%, 11.28%, and 8.33%, respectively. ... However, the MDR1 nt230(del4) [omia.variant:469] was not identified in Border Collies, German Shepherds, White Swiss Shepherds, or Thai Ridgebacks.

Inheritance

The mode of inheritance was initially considered as autosomal recessive. However, Mealey et al. (2003) reported a single dog, who was heterozugous for the ∆MDR1 [omia.variant:469], with increased toxicity of P-glycoprotein-substrate chemotherapeutic agents, and Mealey and Meurs (2008) suggest that 'heterozygous dogs appear to have an intermediate phenotype with respect to responses to avermectins'. Thus an incomplete dominant mode of inheritance may be considered.

Genetic testing

Silvestro et al. (2019) developed two methods for genotyping the deletion variant.

Human analog

OMIA links this condition to its human counterpart in OMIM (Mendelian Inheritance in Man), the place to read across to the deeper human literature for the same biology.

Disease · OMIM 120080 Gene · OMIM 171050

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:001402-9615, doi:10.25910/2AMR-PV70 (CC-BY 4.0).

The evidence

Published references

The peer-reviewed papers behind this disease, curated by OMIA. Starred entries are OMIA-designated landmark papers. Showing 6 of 80.

  1. ★
    Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. · PLoS One · 2016 · PMID 27525650

    Why is this an OMIA Landmark paper? It is "the first large scale report of DNA panel screening across purebred dogs to date", involving the genotyping of 6,788 dogs from 233 breeds for 93 disease-implicated variants across 80 single-locus disorders, providing a very informative "snapshot" of the distribution and frequency of these variants. Importantly, the results indicated "15 risk variants in a total of 34 breeds in which their presence was previously undocumented", which will be very helpful in the provision of genetic counselling in those breeds. The detection of some of these latter variants led to "plausible molecular explanations" for disorders in some breeds.

  2. ★
    Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. · Pharmacogenetics · 2001 · PMID 11692082

    Why is this an OMIA Landmark paper? It is the first to document a likely causal variant for adverse reaction to certain drugs in dogs.

References curated by OMIA (Nicholas, Tammen & the Sydney Informatics Hub), doi:10.25910/2AMR-PV70 (CC-BY 4.0). Full list at the OMIA entry.

Predict a litter

Set each parent's status for MDR1 (Multidrug Resistance 1) Medication Sensitivity and see the odds for their puppies. Single dominant variant, exact Mendelian math.

Parent A
Parent B
NDAffected
NDAffected
NNUnaffected
NNUnaffected
Unaffected50%
Affected50%

These are the genetic odds for one known variant, not a promise: a real litter varies around them, and penetrance or other genes can change whether the condition ever appears. Use it to avoid pairing two carriers and to keep a line healthy, not to engineer a dog. Inheritance mode per OMIA.
Your breed

See what MDR1 (Multidrug Resistance 1) Medication Sensitivity looks like in your dog's breed.
At-risk frequency by breed

Top 25 well-sampled breeds (n ≥ 50)

Maximum at-risk frequency per breed across variants in the Donner 2023 cohort, with . The list below is split into well-sampled breeds (n ≥ 50 tested) and small-sample breeds (n < 50, where the Wilson CI typically spans more than 20 percentage points and frequencies should not be compared directly to the well-sampled entries). Frequencies are population-level, not per-litter or per-line.

0%38%75%
Collie56.4% · n 1,207
Australian Shepherd24.3% · n 2,296
Miniature American Shepherd11.9% · n 1,476
Shetland Sheepdog11.1% · n 945
Old English Sheepdog5.3% · n 423
German Shepherd0.74% · n 15,647
Siberian Husky0.68% · n 9,035
Chow Chow0.47% · n 643
Border Collie0.46% · n 6,712
Norwegian Elkhound0.30% · n 166
Australian Cattle Dog0.25% · n 982
Lhasa Apso0.21% · n 243
Great Pyrenees0.20% · n 1,985
Alaskan Malamute0.20% · n 504
Boxer0.20% · n 4,557
n = 46,821 dogs · Donner et al. 2023 carrier-screening cohort · Sniff Atlas
Each bar is one well-sampled breed; the whisker is its Wilson 95% CI, and fainter bars have wider intervals. Frequencies are population-level, not per-litter. Carrier status for MDR1 (Multidrug Resistance 1) Medication Sensitivity is measured; phenotype outcome depends on penetrance and modifiers.
▸ Full table with Wilson 95% confidence intervals
Breed At-risk frequency n tested
Collie 56.4% 1,207
Australian Shepherd 24.3% 2,296
Miniature American Shepherd 11.9% 1,476
Shetland Sheepdog 11.1% 945
Old English Sheepdog 5.3% 423
German Shepherd 0.74% 15,647
Siberian Husky 0.68% 9,035
Chow Chow 0.47% 643
Border Collie 0.46% 6,712
Norwegian Elkhound 0.30% 166
Australian Cattle Dog 0.25% 982
Lhasa Apso 0.21% 243
Great Pyrenees 0.20% 1,985
Alaskan Malamute 0.20% 504
Boxer 0.20% 4,557
Dobermann Pinscher 0.11% 2,219
American Staffordshire Terrier 0.11% 42,789
Poodle Miniature <0.1% 3,555
Chihuahua <0.1% 4,273
Beagle <0.1% 5,292
Basset Hound <0.1% 990
Labrador Retriever <0.1% 16,853
Bulldog Standard <0.1% 4,816
Golden Retriever <0.1% 12,880
Pembroke Welsh Corgi <0.1% 4,371

Top 25 of 29 well-sampled breeds with at least one observed carrier shown.

▸ Also observed in 1 small-sample breed (n < 50)

Frequencies in this section are statistical estimates with wide Wilson 95% confidence intervals (typically >20 percentage points). Treat these as "at-risk dogs observed but the true population frequency is not yet measurable" rather than as comparable to the well-sampled entries above.

Breed Estimate n tested
Lacy Dog 1.6% 32

236 additional breeds in the Donner 2023 cohort were tested but showed no at-risk genotypes.

Penetrance

From genotype to phenotype

For this dominant trait, a dog with even one copy is at risk, not a silent carrier. Penetrance is the fraction of at-risk dogs that actually develop the phenotype. The Donner 2023 S4 table tracks this for 1 variant(s) underlying this disease in the cohort.

At-risk dogs evaluated
2
Phenotype confirmed
1
Penetrance range
not yet quantifiable

Fewer than 20 at-risk dogs evaluated; too few to state a penetrance figure.

Predicted disease relevance at the per-dog level is UNPROVEN. The at-risk frequency is measured; phenotype outcome is governed by penetrance, environment, and modifier loci. Consult a veterinarian for clinical interpretation.

How to cite this record

Citations

If you use this record in published work, cite the Sniff Atlas (the published dataset that carries the breed-level carrier frequencies) and the upstream sources:

  • Sniff Atlas v1.0.1 for the per-breed carrier frequencies:

    Gehring, M. (2026). Sniff Atlas v1.0.1. Zenodo. https://doi.org/10.5281/zenodo.20566358. CC-BY 4.0.

  • OMIA for the disease definition, inheritance, and gene assignment:

    Nicholas, F. W., & Tammen, I. (2024). OMIA. Sydney Informatics Hub, The University of Sydney. https://doi.org/10.25910/2AMR-PV70. Entry: OMIA:001402-9615.

  • Donner et al. 2023 for the breed × variant carrier-frequency cohort:

    Donner, J., Freyer, J., Davison, S., Anderson, H., Blades, M., Honkanen, L., et al. (2023). Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLOS Genetics, 19(2), e1010651. https://doi.org/10.1371/journal.pgen.1010651.

Full citation formats (BibTeX, RIS, CITATION.cff) at sniff.world/cite.

Related

Related

Last updated
Sources: Sniff Atlas v1.0.1 · OMIA OMIA:001402-9615 · Donner et al. 2023