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 (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.