Photo by Rice Paice
Thankfully, Deerhounds do NOT have the MDR1 mutation.
by John Dillberger, DVM, PhD
Reprinted from the November/December 2022 issue of The Claymore.
This month’s column is about a heritable health problem that Deerhounds do NOT have. We know this because of a research project conceived by the SDCA, conducted by Washington State University (WSU), and funded by your donations to our Health Fund.
If you think the absence of a health problem is not news at all, then think again. This is a health research success story about an effective collaboration to investigate a potentially important health problem. And the story begins with a drug called ivermectin.
In the 1980s, Merck brought to market a revolutionary new drug called ivermectin. A single pill protects dogs against heartworm infection for a month. Ivermectin lingers in a dog’s blood for weeks, killing any heartworm larvae before they can mature into adults. The drug short‑circuits the larva’s nervous system to cause lethal paralysis.
Ivermectin also can affect a dog’s nervous system, but it normally is safe for two reasons. First, ivermectin targets a part of the dog’s nervous system confined to the brain. Second, little ivermectin reaches the brain because of something called the blood-brain barrier (BBB).
The BBB is not a physical barrier but a functional one that limits the movement of substances from the blood into the brain itself. A key component of the BBB is a molecule called P-glycoprotein. P‑glycoprotein belongs to a class of proteins called drug transporters, which use energy to move molecules across cell membranes. P-glycoprotein sits in the walls of blood vessels that supply the brain, where it pumps ivermectin (and many other drugs) out of the brain and back into the blood. As a result, ivermectin is effectively stopped from entering the brain.
Not long after ivermectin was introduced, reports began to appear of Collies being poisoned by it. From the symptoms, the illness involved the nervous system. Later, the same sort of ivermectin sensitivity was seen in Australian Shepherds, Shetland Sheepdogs, and Old English Sheepdogs.
Eventually ivermectin sensitivity was found to be due to a mutation in the MDR1 gene, the blueprint for making P-glycoprotein. The defective P-glycoprotein allows ivermectin to build up and reach toxic levels in the brain. Affected dogs also are sensitive to other drugs transported by P-glycoprotein, which they must either avoid or take at lower doses.
Several different mutations have been found in the MDR1 gene, and the different variants are collectively designated as mdr1-1D. A genetic analysis conducted in 4,000 dogs across numerous breeds (Neff et al., 2004) found the mdr1-1D variant in 9 breeds. Besides the breeds mentioned earlier, the variant was found in three other Collie-related herding breeds (Miniature Australian Shepherd, English Shepherd, McNab) and in two sighthound breeds: the Long-haired Whippet and the Silken Windhound. Since 2004, the mdr1-1D variant also has been found in mixed breed dogs of suspected Collie heritage and in boxers.
From their analysis, Neff and his colleagues concluded that the mdr1-1D variant “was not an ancient allele (e.g., one introduced into the British Isles by Roman or Viking dogs).” Instead, the mutation arose in a dog belonging to “an admixed population of working sheepdogs” that “lived in Great Britain in the 1800s, before the emergence of formal breeds.” As the authors put it (with tongue in cheek), this original ancestor dog “experienced remarkable evolutionary success, having contributed genetically to at least nine distinct breeds of dog” that exist today.
The Deerhound Story
Do Deerhounds carry the mdr1-1D variant? There is evidence that “working sheepdogs” could figure in the genetic history of at least some of today’s Scottish Deerhounds. For example, the only disqualification for exhibiting a Deerhound in a dog show, written into the original standard in the 19th century, is “white blaze on the head, or a white collar.” The intent was to exclude crossbreeds with sheepdog in their background. This raises the possibility that the mdr1-1D variant might have snuck into the Deerhound population.
With the approval of the SDCA Board, the Health and Genetics Committee recently decided to address this question. No one on the committee had heard of ivermectin sensitivity in a Deerhound or a Deerhound that had been found to carry the mdr1-1D variant. But we realized that a case of ivermectin sensitivity in the breed might have gone unrecognized or unreported. We also suspected that very few Deerhounds had ever been tested for the mdr1-1D variant.
We decided to collaborate with WSU to screen 296 Deerhound DNA samples, which were banked there as part of the SDCA-sponsored study on delayed postoperative bleeding. WSU has been at the forefront of MDR1 mutation research across breeds.
The result was the best we could hope for. None of the 296 Deerhounds tested had the mdr1-1D variant. While not conclusive, this information strongly suggests that the mdr1-1D variant is absent in Deerhounds – or at least in the North American population, from which most of the samples were collected.
A Parting Thought
Neff and his colleagues discuss what their work reveals about the history and derivation of herding breeds in Great Britain. And they also suggest a new approach to studying the history of dog breeds in general:
“Geneticists have previously attempted to describe canine breed ancestry by averaging the phylogenetic results of marker loci distributed across the genome, thereby characterizing breeds as monophyletic. We prefer to view dog breeds not as… subspecies, but rather as dynamic populations that have historically experienced admixture, introgression, and genetic isolation. …[D]ifferent regions of the canine genome have distinct evolutionary histories (i.e., polyphyletic). Accordingly, breed phylogeny per se is perhaps less relevant than the phylogeny of individual traits. Each polymorphism, especially those of phenotypic effect, will recount an interesting story about the history of dogs and the origin of traits.” [italics mine]
Reference
Neff MW, Robertson KR, Wong AK, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC (2004). Breed distribution and history of canine mdr1-1D, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. PNAS 101 (32): 11725-11730.