Breed distribution of the nt230(del4) MDR1 mutation in dogs

Abstract

A 4-bp deletion mutation associated with multiple drug sensitivity exists in the canine multidrug resistance (MDR1) gene. This mutation has been detected in more than 10 purebred dog breeds as well as in mixed breed dogs. To evaluate the breed distribution of this mutation in Germany, 7378 dogs were screened, including 6999 purebred and 379 mixed breed dogs. The study included dog breeds that show close genetic relationship or share breeding history with one of the predisposed breeds but in which the occurrence of the MDR1 mutation has not been reported. The breeds comprised Bearded Collies, Anatolian Shepherd Dog, Greyhound, Belgian Tervuren, Kelpie, Borzoi, Australian Cattle Dog and the Irish Wolfhound.

The MDR1 mutation was not detected is any of these breeds, although it was found as expected in the Collie, Longhaired Whippet, Shetland Sheepdog, Miniature Australian Shepherd, Australian Shepherd, Wäller, White Swiss Shepherd, Old English Sheepdog and Border Collie with varying allelic frequencies for the mutant MDR1 allele of 59%, 45%, 30%, 24%, 22%, 17%, 14%, 4% and 1%, respectively. Allelic frequencies of 8% and 2% were determined in herding breed mixes and unclassified mixed breeds, respectively.

Because of its widespread breed distribution and occurrence in many mixed breed dogs, it is difficult for veterinarians and dog owners to recognise whether MDR1-related drug sensitivity is relevant for an individual animal. This study provides a comprehensive overview of all affected dog breeds and many dog breeds that are probably unaffected on the basis of ∼15,000 worldwide MDR1 genotyping data.

Introduction

P-glycoprotein is an adenosine triphosphate (ATP)-driven drug efflux carrier, encoded by the multidrug resistance gene MDR1, also referred to as ABCB1. P-glycoprotein transports a broad variety of structurally diverse compounds that are usually hydrophilic and amphiphatic (Fromm, 2004), including many drugs commonly used in veterinary medicine (Mealey, 2004). The carrier is expressed in many tissues with secretory or excretory functions, such as the liver, kidney and intestine, where it limits drug absorption from the gut and promotes drug excretion into the bile and urine. Additionally, P-glycoprotein is highly expressed at the blood–brain barrier, where it restricts drug entry into the central nervous system (Thiebaut et al., 1987, Cordon-Cardo et al., 1990).

In 2001, a 4-bp gene deletion mutation was identified in the canine MDR1 gene and was referred to as mdr1-1Δ, ABCB1-1Δ, or MDR1 nt230(del4) (Mealey et al., 2001, Neff et al., 2004, Geyer et al., 2005a, Mealey and Meurs, 2008). This MDR1 mutation correlates with the ivermectin-sensitive phenotype that was recognised in Collie dogs in the early 1980s (Seward, 1983, Pulliam et al., 1985). Dogs with homozygous nt230(del4) MDR1 mutations do not express a functionally intact P-glycoprotein and (in addition to ivermectin) show increased sensitivity to many P-glycoprotein-transported drugs such as moxidectin, milbemycin oxime, acepromazine, butorphanol, digoxin, vincristine and loperamide (Martinez et al., 2008, Mealey, 2008).

Apart from the Collie, many additional dog breeds as well as mixed breed dogs are affected by this mutation (Neff et al., 2004, Geyer et al., 2005b, Mealey and Meurs, 2008) and it is therefore difficult for veterinarians and dog owners to recognise whether MDR1-related drug sensitivity is relevant for an individual animal. The purpose of the present study was to provide an overview of all affected as well as many of the most likely unaffected dog breeds on the basis of 7378 MDR1 genotyping data from Germany and an additional 7500 cases reported in the literature from other countries.