In other species: dog , taurine cattle , goat

Categories: Homeostasis / metabolism phene

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

Single-gene trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Cross-species summary: MDR1

Inheritance: A recessive mode of inheritance has been considered. In other species an incomplete dominant mode of inheritance is discussed.

Molecular basis: By sequencing the most obvious functional candidate gene in 8 cats that showed "adverse reactions to P-glycoprotein substrate drugs" (including one sensitive to ivermectin), Mealey and Burke (2015) discovered a 2bp deletion in the ABCB1 gene (11930_1931del TC) that was homozygous in the one cat sensitive to ivermectin. However, the other 7 sensitive cats were homozygous for a normal functional ABCB1 allele. In addition, "14 missense mutations were identified in one or more phenotyped cats". Mealey et al. (2021) investigated “whether ABCB11930_1931del TC predisposed cats to macrocyclic-lactone toxicosis and the frequency of the ABCB11930_1931del TC gene mutation in banked feline DNA samples. … 4 of the 5 cats with neurologic signs presumed to be associated with macrocyclic-lactone exposure were homozygous for ABCB11930_1931del TC. The other cat had unilateral vestibular signs not typical of macrocyclic-lactone toxicosis. … Results suggested a strong relationship between homozygosity for ABCB11930_1931del TC and neurologic toxicosis after topical application with eprinomectin-containing antiparasitic products labeled for use in cats … .”

Clinical features: Multidrug resistance 1 results in higher risk of adverse drug reactions to P-glycoprotein substrate drugs such as ivermectin and macrocyclic lactones due to impaired P-glycoprotein synthesis. These drugs are commonly found in flea and tick preventatives for cats and dogs (Mealey et al., 2023). Clinical effects can be neurological such as CNS depression, ataxia, seizure activity, tremors, hypersalivation, vomiting, mydriasis, dyspnoea, and in severe cases, coma, blindness and death. It can also manifest in bone marrow suppression in the form of neutropenia and thrombocytopenia. Gatstrointestinal toxicity has also been reported (Mealey et al., 2021). IT thanks DVM student Wen Yee Tan, who provided the basis of this contribution in May 2023.

Prevalence: Mealey et al. (2021): "The distribution of genotypes from the banked feline DNA samples was as follows: 0 homozygous for ABCB11930_1931del TC, 47 heterozygous for ABCB11930_1931del TC, and 959 homozygous for the wild-type ABCB1 allele. Among the 47 cats with the mutant ABCB1 allele, only 3 were purebred (Ragdoll, Russian Blue, and Siamese)."

Breeds: Balinese (Cat) (VBO_0100036), Domestic Longhair, Domestic medium-haired, Domestic Shorthair, Maine Coon (Cat) (VBO_0100154), Maine Coon Polydactyl (Cat) (VBO_0100155), Ragdoll (Cat) (VBO_0100196), Russian Blue (Cat) (VBO_0100200), Siamese (Cat) (VBO_0100221), Turkish Angora (Cat) (VBO_0100249).
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: