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Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene
K L Mealey1, S A Bentjen, J M Gay
1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-6610, USA. kmealey@vetmed.wsu.edu
Abstract:
A subpopulation of collie dogs is extremely sensitive to neurotoxicity induced by ivermectin. The aim of this study was to determine the mechanistic basis for this phenomenon. The multi-drug-resistance gene (mdr1) encodes a large transmembrane protein, P-glycoprotein (P-gp), that is an integral part of the blood-brain barrier. P-gp functions as a drug-transport pump at the blood-brain barrier, transporting a variety of drugs from the brain back into the blood. Since ivermectin is a substrate for P-gp, we hypothesized that ivermectin-sensitive collies had altered mdr1 expression compared with unaffected collies. We report a deletion mutation of the mdr1 gene that is associated with ivermectin sensitivity. The 4-bp deletion results in a frame shift, generating several stop codons that prematurely terminate P-gp synthesis. Dogs that are homozygous for the deletion mutation display the ivermectin-sensitive phenotype, while those that are homozygous normal or heterozygous do not display increased sensitivity to ivermectin.
Insights
A specific mutation in the multi-drug-resistance gene (mdr1) causes ivermectin sensitivity in collie dogs. This deletion prevents the production of P-glycoprotein, a key blood-brain barrier transporter.
Area of Science:
- Veterinary Pharmacology
- Canine Genetics
- Neurotoxicology
Background:
- Collie dogs exhibit extreme sensitivity to ivermectin-induced neurotoxicity.
- The multi-drug-resistance gene (mdr1) encodes P-glycoprotein (P-gp), a crucial efflux pump at the blood-brain barrier.
- P-gp actively transports various substances, including ivermectin, out of the brain.
Purpose of the Study:
- To elucidate the mechanistic basis of ivermectin sensitivity in a subpopulation of collie dogs.
- To investigate the role of the mdr1 gene in ivermectin neurotoxicity.
Main Methods:
- Comparative analysis of mdr1 gene expression in ivermectin-sensitive versus unaffected collies.
- Identification and characterization of genetic mutations within the mdr1 gene.
- Genotyping to correlate mdr1 mutations with ivermectin sensitivity phenotype.
Main Results:
- A specific 4-base pair deletion mutation in the mdr1 gene was identified and associated with ivermectin sensitivity.
- This deletion causes a frameshift, leading to premature termination of P-gp synthesis.
- Homozygosity for the deletion mutation correlates with the ivermectin-sensitive phenotype; heterozygotes and homozygous normal dogs are unaffected.
Conclusions:
- The identified mdr1 deletion mutation is the mechanistic cause of ivermectin sensitivity in collies.
- Impaired P-gp function due to this mutation compromises the blood-brain barrier's ability to exclude ivermectin.
- Genetic screening for the mdr1 deletion can identify collies at risk for ivermectin neurotoxicity.