Original ArticlesIvermectin sensitivity in collies is associated with a deletion mutation of the mdr1 geneMealey, Katrina L.a; Bentjen, Steve A.a; Gay, John M.a; Cantor, Glenn H.b Author Information Departments of aVeterinary Clinical Sciences and bVeterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA Correspondence to Katrina L. Mealey, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA Fax: +1 509 335 0880; email: [email protected] Received 7 March 2001 Accepted 30 April 2001 Pharmacogenetics 11(8):p 727-733, November 2001. Buy 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 (mdr 1) 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 mdr 1 expression compared with unaffected collies. We report a deletion mutation of the mdr 1 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. © 2001 Lippincott Williams & Wilkins, Inc.