{"id":2526,"date":"2017-09-01T08:51:12","date_gmt":"2017-09-01T12:51:12","guid":{"rendered":"http:\/\/phosdev.com\/todaysveterinarynurse\/?post_type=articles&p=2526"},"modified":"2022-05-03T18:23:26","modified_gmt":"2022-05-03T18:23:26","slug":"mdr1-genetic-testing","status":"publish","type":"post","link":"https:\/\/navc.sitepreview.app\/todaysveterinarynurse.com\/clinical-pathology\/mdr1-genetic-testing\/","title":{"rendered":"MDR1 Genetic Testing: What You Need to Know"},"content":{"rendered":"

The American Kennel Club currently recognizes 30 breeds of dogs in its herding-breed group. Within that group are some of the most recognizable and beloved dog breeds in the world, including the collie and Australian shepherd. These dogs are common patients in most veterinary practices.<\/p>\n

The study of genetics is revealing more about canine history and health than ever before. For example, hidden in the genetic code of many herding-breed dogs is a mutation that increases their susceptibility to drug toxicosis. Public awareness about this defect is increasing, but many websites dispense confusing information to breeders and owners. As an important component of client communication in the veterinary hospital, veterinary technicians can help sort out misinformation and assist clients in making decisions about the health of their dog. In addition, technicians must recognize which dogs are at risk and which drugs to avoid or administer with a reduced dose.<\/p>\n

MDR1<\/em> Mutation<\/h2>\n

In 2001, Katrina Mealey, DVM, PhD, discovered that collies and other dogs with herding-breed heritage have a defect in the MDR1<\/em> (multidrug resistance 1) gene.1<\/sup> The nomenclature for the MDR1<\/em> gene also includes the designation ABCB1<\/em> gene (adenosine triphosphate\u2013binding cassette transporter). The MDR1<\/em> mutation causes a change in the code for an important component of the blood\u2013brain barrier, P-glycoprotein.<\/p>\n

P-glycoprotein<\/h3>\n

In normal dogs, P-glycoprotein functions as a pump, moving potentially toxic compounds out of the central nervous system (CNS). It also transports substrate drugs across cell membranes and out of the body. This occurs at the level of biliary canaliculi, intestinal epithelial cells, and renal proximal tubular epithelial cells. Prescribed medications can therefore behave in a predictable manner when proper dosing instructions are followed.<\/p>\n

However, when the MDR1<\/em> mutation is present, P-glycoprotein is severely truncated, rendering it ineffective. Substrates for P-glycoprotein, including many common medications, remain in the CNS at toxic levels or are otherwise incorrectly metabolized or excreted. This can lead to severe and potentially fatal adverse drug reactions. Additionally, further research has revealed that P-glycoprotein plays a role in the regulation of the hypothalamic-pituitary-adrenal axis.2<\/sup> In dogs that are homozygous for the MDR1<\/em> mutation (BOX 1)<\/strong>, this important hormonal feedback system does not function normally, causing lower cortisol levels. The effects become apparent under periods of high stress, such as illness or extreme physical activity. These dogs may respond poorly to such increased energy demands and exhibit evidence of relative adrenal insufficiency. In some cases, physiologic doses of corticosteroids are indicated.<\/p>\n

<\/strong>BOX 1<\/strong> Inheritance of MDR1<\/em> Mutation<\/div>
<\/strong><\/p>\n

Just like people, dogs inherit 1 copy of a gene from the father and 1 from the mother. A complete genome therefore contains 2 copies of each gene (1 from each parent). If a dog inherits 1 normal copy of the gene and 1 mutant copy, the dog is considered heterozygous for the mutation and is reported as mutant\/normal. A dog with 2 abnormal copies is called homozygous, or mutant\/mutant. A dog that does not carry any copies of the mutation is referred to as normal\/normal.<\/p>\n

It is confusing to refer to genetic results as \u201cpositive\u201d or \u201cnegative\u201d because the meaning in some contexts can be ambiguous. Similarly, the MDR1<\/em> mutation is a dominant genetic trait, so the use of the word \u201ccarrier\u201d for heterozygous dogs is incorrect. Both heterozygous and homozygous dogs can show drug toxicosis when given P-glycoprotein substrates.<\/p>\n

<\/div><\/div><\/strong><\/p>\n

Affected Breeds<\/h2>\n

In the 1980s, when new parasiticides, such as ivermectin, were introduced, collie owners and veterinarians began reporting adverse drug reactions. Dog owners attempted to identify which dogs were most likely to have a reaction by using phenotypic qualities, such as coat color or markings. A common adage at the time was \u201cwhite feet, don\u2019t treat,\u201d meaning that dogs with white feet were thought to be more susceptible to ivermectin toxicity.<\/p>\n

Because of early reports of ivermectin toxicity in collies, that breed became the early model for researchers to discover more about this genetic mutation. It became clear that not only collies, but also other herding-breed dogs, possessed this abnormal genetic code.<\/p>\n

A Herding Dog Gene<\/h3>\n

By using advanced evolutionary genetic techniques, scientists traced the history of this mutation over time.3<\/sup> It first appeared in a herding dog in Great Britain in the late 19th century, before the collie breed even originated. This anonymous dog may have possessed some desirable feature or skill, which meant that it passed its genes on to numerous descendants. Unknown to generations of breeders, the MDR1<\/em> mutation was passed on as well.<\/p>\n

Eventually, dog breeds became more clearly defined. As new breeds developed from older ones, the genetic heritage followed. By analyzing how far back in the canine family tree a breed broke off from the foundation stock, geneticists can predict which descendant breeds potentially carry the mutation (BOX 2)<\/strong>.<\/p>\n

<\/strong>BOX 2<\/strong> Collie Family Tree<\/div>
<\/strong><\/p>\n

The historic relationships between contemporary collie breeds are shown in the University of California, Davis breed descendant tree in FIGURE A<\/strong>. This is a simplified form; there have been other, lesser influences. Many breeds in addition to collie breeds are descended from the Roman cattle dogs, herding spitzes, and Celtic dogs. However, this tree shows only the collie and collie-related breeds that descended from the working shepherd dogs\/collies of Great Britain.<\/p>\n

This tree is not meant to imply that there was only one type of each ancestral shepherd dog. Throughout Britain there were many local variations\/subtypes between and within regions, as well as common types across and within regions, a situation that is too complicated to be shown on this simple relationship chart.<\/p>\n

\"FIGURE<\/a>

FIGURE A.<\/strong> University of California, Davis breed descendant tree. This chart shows historic relationships between contemporary collie breeds. *Selection for show by 1990, in some cases well before. Reprinted with permission of the creator, Linda Rorem.<\/em><\/p><\/div>\n

<\/div><\/div><\/strong><\/p>\n

The MDR1<\/em> mutation has been identified in 10 herding breeds, 2 sighthound breeds, and herding-breed mixed dogs (TABLE 1)<\/strong>.4<\/sup> Collies have one of the highest frequencies\u2014approximately 70% are homozygous or heterozygous for the mutation. Australian shepherds and Shetland sheepdogs are also affected. The high incidence of the MDR1<\/em> mutation in long-haired whippets and silken windhounds is believed to be due to use of an affected herding dog to introduce a desirable trait at some point in the breed\u2019s history.<\/p>\n

 <\/p>\n

TABLE 1 <\/strong>Breeds Affected by the MDR1<\/em> Mutation<\/strong>4<\/sup><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
BREED<\/strong><\/td>\nAPPROXIMATE FREQUENCY (%)<\/strong><\/td>\n<\/tr>\n<\/thead>\n
Collie<\/td>\n70<\/td>\n<\/tr>\n
Long-haired whippet<\/td>\n65<\/td>\n<\/tr>\n
Australian shepherd<\/td>\n50<\/td>\n<\/tr>\n
Australian shepherd, mini<\/td>\n50<\/td>\n<\/tr>\n
McNab collie<\/td>\n30<\/td>\n<\/tr>\n
Silken windhound<\/td>\n30<\/td>\n<\/tr>\n
English shepherd<\/td>\n15<\/td>\n<\/tr>\n
Shetland sheepdog<\/td>\n15<\/td>\n<\/tr>\n
German shepherd<\/td>\n10<\/td>\n<\/tr>\n
Herding-breed cross<\/td>\n10<\/td>\n<\/tr>\n
Mixed breed<\/td>\n5<\/td>\n<\/tr>\n
Old English sheepdog<\/td>\n5<\/td>\n<\/tr>\n
Border collie<\/td>\n<5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Drugs Affected<\/h2>\n

Ivermectin<\/h3>\n

Ivermectin is the drug most commonly associated with toxicosis, although many other drugs may also cause adverse reactions (BOX 3)<\/strong>.5<\/sup> Because of the public\u2019s awareness of ivermectin-associated problems, many breeders and websites recommend avoiding all products containing this drug, including heartworm preventive agents. It is true that higher concentrations of ivermectin, such as those used for treating mange and other parasites, should not be administered to MDR1<\/em>-affected dogs. However, dog owners should know that the doses of US-produced heartworm preventive agents recommended by manufacturers and approved by the Food and Drug Administration are safe for dogs with the mutation.<\/p>\n

<\/strong>BOX 3<\/strong> Drugs Affected by the MDR1<\/em> Gene Mutation5<\/sup><\/div>
<\/strong><\/p>\n