Abstract
BackgroundSensitivity to macrocyclic lactones, which are commonly used in veterinary clinics, was first found in Rough Collies, and was attributed in 2001 to a 4 bp deletion in the MDR1 gene. The list of affected breeds currently includes 13 breeds. Researchers from different countries and continents examined the allelic frequencies of the nt230(del4) MDR1 mutation, emphasizing the clinical importance of this test not only to mutation-prone dogs, but also to their crosses and mongrels, since treatment of a deletion carrier with these compounds may lead to its death.In this study, the allelic frequencies of nt230(del4) MDR1 mutation in affected breeds, their crosses, unrelated pure breeds and mongrels are reported for the state of Israel (n = 1416 dogs). The Israeli data were compared with reports from the US, Europe, UK, Australia and Japan.ResultsThe allelic frequencies of nt230(del4) MDR1 mutation in Israel for Australian, Swiss and German Shepherds (31%, 17% and 2.4%, respectively) are similar to the corresponding frequencies worldwide, much higher for Border Collies (4.8%), twice lower for Rough Collies (28%, compared to 55% or more elsewhere), and ~1% for mongrels. The frequencies for crosses of Australian Shepherd and Border Collies in Israel are 4 and 1.6 times lower, respectively, compared to the frequencies for the respective pure breeds.ConclusionsThis work, that for the first time presents the frequency of nt230(del4) MDR1 mutation in Israel, along with a worldwide survey, has implications for clinicians, owners and breeders of sheepdogs and their crosses and supports the need for extra care in treatment and in future breeding. Of note, the relative proportion of affected breeds, in the overall tested dogs, might be higher than their actual proportion in Israel due to directed samples collection by veterinarians for clinical purposes, as these are mainly limited to certain affected breeds or dogs that resemble them.
Highlights
Sensitivity to macrocyclic lactones, which are commonly used in veterinary clinics, was first found in Rough Collies, and was attributed in 2001 to a 4 bp deletion in the multi drug resistance 1 (MDR1) gene
While MDR1 activity in the small intestine can limit the bioavailability of various drugs, its inactivity in the luminal membranes of the endothelial cells of the brain can lead to toxic accumulation of xenobiotics in the central nervous system (CNS) and to severe adverse effects, including death [6, 7]
In 2001, ivermectin sensitivity in Rough Collies was associated with a 4-base pair deletion mutation in the fourth exon of the canine ABC subfamily B member 1 (ABCB1) gene [11]
Summary
Sensitivity to macrocyclic lactones, which are commonly used in veterinary clinics, was first found in Rough Collies, and was attributed in 2001 to a 4 bp deletion in the MDR1 gene. Later studies showed that nt230(del4) MDR1 mutation heterozygous dogs can be regarded as having an intermediate macrocyclic lactone sensitive phenotype This is a relevant clinical notion in cases of high-dose protocols [6, 13]. Other drugs commonly used in the veterinary clinic, such as P-glycoprotein substrates of the non-macrocyclic lactones type, were reported as toxic to nt230(del4) MDR1 mutation homozygote dogs (−/−). These include vincristine, digoxin, mexiletine, quinidine, fexofenadine, vinblastine, and loperamide, cyclosporine A, verapamil, paclitexal, doxorubicin, dexamethasone and others [14,15,16,17,18,19]. Based on its antiparasitic and anti-inflammatory activities, ivermectin has recently received US Food and Drug Administration (FDA) and EU approval for the treatment of adult human patients for a growing number of indications [24]
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