In other species: domestic cat , taurine cattle , goat

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 171050 (gene) , 120080 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2001

Cross-species summary: MDR1

Species-specific name: Ivermectin sensitivity

Species-specific description: 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.

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.

Molecular basis: 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".

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]

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.

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

Breeds: Australian Shepherd (Dog) (VBO_0200095), Border Collie (Dog) (VBO_0200193), Collie (Dog) (VBO_0200375), Collie Rough (Dog) (VBO_0200376), German Shepherd Dog (Dog) (VBO_0200577), Huntaway (Dog) (VBO_0200683), Long-Haired Whippet (Dog) (VBO_0200833), McNab Shepherd (Dog) (VBO_0200872), Miniature Australian Shepherd Dog (Dog) (VBO_0200881), Mixed Breed (Dog) (VBO_0200902), Old English Sheepdog (Dog) (VBO_0200969), Shetland Sheepdog (Dog) (VBO_0201217), Silken Windhound (Dog) (VBO_0201235), Waller (Dog) (VBO_0201394), White Swiss Shepherd Dog (Dog) (VBO_0201423).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: