title: Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene.
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.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-6610, USA. kmealey@vetmed.wsu.edu
authors.forename: K L
authors.initials: KL
authors.lastname: Mealey
authors.forename: S A
authors.initials: SA
authors.lastname: Bentjen
authors.forename: J M
authors.initials: JM
authors.lastname: Gay
authors.forename: G H
authors.initials: GH
authors.lastname: Cantor
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D000969:Antinematodal Agents / Q000008:administration & dosage / Q000009:adverse effects; D001483:Base Sequence; D004283:Dog Diseases / Q000235:genetics / Q000517:prevention & control; D004285:Dogs / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D017353:Gene Deletion; D019450:Genes, MDR / Q000235:genetics*; D007559:Ivermectin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008969:Molecular Sequence Data; D009349:Nematode Infections / Q000235:genetics / Q000517:prevention & control / Q000662:veterinary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000969:Antinematodal Agents; D007559:Ivermectin