Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene

A subpopulation of collie dogs is extremely sensitive to neurotoxicity indu ced by ivermectin. The aim of this study was to determine the mechanistic b asis for this phenomenon. The multi-drug-resistance gene (mdr1) encodes a l arge 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 i nto the blood. Since ivermectin is a substrate for P-gp, we hypothesized th at ivermectin-sensitive collies had altered mdr1 expression compared with u naffected collies. We report a deletion mutation of the mdr1 gene that is a ssociated with ivermectin sensitivity. The 4-bp deletion results in a frame shift, generating several stop codons that prematurely terminate P-gp synt hesis. Dogs that are homozygous for the deletion mutation display the iverm ectin-sensitive phenotype, while those that are homozygous normal or hetero zygous do not display increased sensitivity to ivermectin. Pharmacogenetics 11:727-733 (C) 2001 Lippincott Williams & Wilkins.