Novel insertion mutation ofABCB1gene in an ivermectin-sensitive Border Collie

Abstract

P-glycoprotein (P-gp) is encoded by the ABCB1 gene and acts as an efflux pump for xenobiotics. In the Border Collie, a nonsense mutation caused by a 4-base pair deletion in the ABCB1 gene is associated with a premature stop to P-gp synthesis. In this study, we examined the full-length coding sequence of the ABCB1 gene in an ivermectin-sensitive Border Collie that lacked the aforementioned deletion mutation. The sequence was compared to the corresponding sequences of a wild-type Beagle and seven ivermectin-tolerant family members of the Border Collie. When compared to the wild-type Beagle sequence, that of the ivermectin-sensitive Border Collie was found to have one insertion mutation and eight single nucleotide polymorphisms (SNPs) in the coding sequence of the ABCB1 gene. While the eight SNPs were also found in the family members' sequences, the insertion mutation was found only in the ivermectin-sensitive dog. These results suggest the possibility that the SNPs are species-specific features of the ABCB1 gene in Border Collies, and that the insertion mutation may be related to ivermectin intolerance.

Epidemiological study (2006–2012) on the poisoning of small animals by human and veterinary drugs

“…Macrocyclic lactones are commonly used as nematicides and acaricides in animals, and acute toxicoses with CNS clinical signs were more often encountered with ivermectin (Gwaltney‐Brant and others 2012, Siroka and Svobodova 2013). Collies are especially known for their breed‐dependent adverse reaction to ivermectin (Hopper and others 2002, Nelson and others 2003, Berny and others 2010, Han and others 2010, Siroka and Svobodova 2013), but other breeds (Lehner and others 2009, Merola and others 2009, Bates and others 2013, Siroka and Svobodova 2013) as well as cats (Nelson and others 2003) were reported to be sensitive to ivermectin toxicosis. Except for one recorded case of cat exposure to selamectin, a new semi‐synthetic avermectin, all other cases involved dogs with predominant incidence of ivermectin, with only one case of exposure to mylbemicin oxime (Barbet and others 2008) and selamectin.…”

Rapid genotyping assays for the 4–base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs

“…2 Recently, a novel insertion mutation of the canine MDR1 gene was identified in an ivermectinsensitive Border Collie, although the correlation between the insertion mutation and the ivermectin-sensitive phenotype in this dog was not clarified completely. 13 In human beings, at least 3 single nucleotide polymorphisms were found in the human MDR1 gene, 17 which may be related to abnormal sensitivity to multiple drugs. Furthermore, except for P-gp, other drug-efflux transporters such as multidrug-resistance proteins or organic anion transporting polypeptides are expressed at the blood-brain barrier and these transporters function supportively to prevent entry of xenobiotics from free access to the central nervous system.…”

Toxicology of Avermectins and Milbemycins (Macrocylic Lactones) and the Role of P-Glycoprotein in Dogs and Cats

“…55 Interestingly, in both of these studies, it was rare (about 1% frequency) to find the ABCB1 mutation in border collies. However, a recent report of an ABCB1 mutation that differs from the ABCB1-1 Δ mutation in an ivermectin-sensitive border collie 56 demonstrates that other gene defects can produce the ivermectin-sensitive phenotype. Thus, just because a dog does not have the ABCB1-1 Δ genotype does not mean that it is absolutely certain that it will tolerate higher dosages of MLs.…”