Loss-of-function mutation in the ABCB1 gene (formerly MDR1) that encodes P-glycoprotein, a drug efflux pump present in the blood-brain barrier. Without this pump, certain drugs (ivermectin and other endectocides, loperamide, some chemotherapeutic agents such as doxorubicin/vincristine and certain anaesthetics) accumulate in the central nervous system, causing neurotoxicity that can be fatal. It is not a structural disease: it is an inherited pharmacogenetic condition, and knowing about it prevents severe iatrogenic poisonings.

Historically high mutant allele frequencies in long-haired Collie, Shetland Sheepdog, Border collie (low but present), Australian Shepherd, Old English Sheepdog (Bobtail), long-haired Whippet, Silken windhound, white Swiss shepherd, Mc Nab and Elo; also described in Walliser-Sennenhund. Systematic screening in organised breeds has greatly reduced the frequency of homozygotes. The specific percentages per population are not cited here: limited data.

- Poisoning after administration of ivermectin/moxidectin/doramectin at high or cumulative doses: tremors, myasthenia, excessive salivation, mydriasis, ataxia, seizures, coma.\n- Sensitivity also to loperamide (opioid antidiarrhoeal), emodepside, spinosad and various cytostatics/anaesthetics.\n- Heterozygotes may show signs at high doses (intermediate penetrance of the pharmacological phenotype).\n- Outside pharmacological exposures, the dog is completely healthy.

Abnormal sensitivity to ivermectin in Collies had been known since the 1980s as a clinical phenomenon without explanation. In 2001, Katrina Mealey (Washington State University) demonstrated that the cause was a 4-base-pair deletion in the MDR1 gene perfectly associated with the sensitive phenotype in Collies (Mealey KL et al., Pharmacogenetics 2001). It was a founding milestone of veterinary pharmacogenetics: for the first time a genetic test explained adverse drug reactions in companion animals. The same mutation was subsequently confirmed in numerous herding breeds of British origin and in long-haired sighthounds, the groups of drugs involved (P-gp substrates) were characterised, and Washington State University established the world reference registry for the test.

- Test ALL breeding lines of affected breeds before the first mating.\n- Clear × carrier: acceptable, progressively replacing offspring with clear animals.\n- Carrier × carrier and affected × anything: avoid (risk of Δ/Δ puppies exposed to everyday drugs).\n- Record the status in health booklets and communicate it to every veterinarian who attends the animal throughout its life.\n- In breeds with a high frequency (Collie, Sheltie), keep updated lists of breeding dogs and use clear males whenever possible to accelerate the reduction of the allele.

Official list of problematic drugs maintained by WSU (P-gp substrates): avermectins/milbemycins at high antiparasitic doses, loperamide, acepromazine and butorphanol (caution), quinidine, doxorubicin, vincristine, vinblastine, Actinomycin D, mitoxantrone, emodepside. Diagnostic alternative to the DNA test: fluorescence functional test (does not replace genotyping for breeding). Consider pre-anaesthetic and pre-chemotherapy genotyping in at-risk breeds even if the owner does not request it.

1. Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001.. PMID: 11692082
2. Mealey KL. Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther. 2004.. PMID: 15500562