Groundbreaking discovery leads to genetic test for EIC in Labrador retrievers

05/20/2010

LabJudy and Jim Powers, Sheboygan, Wis., understand firsthand the heartbreak of buying a dog affected with exercise-induced collapse (EIC). EIC, the once-puzzling neurological syndrome, has become prevalent in pedigreed Labrador retrievers over the past couple of decades. "The dog we had that was affected with EIC could have been a competitive dog," says Judy. But he never got the chance. As the 3-year-old dog progressed through more rigorous training exercises, he started to exhibit signs of the dreaded condition, weakness in the rear limbs during strenuous exercise that can spread to the forelimbs. If not immediately rested, the dog would collapse. After making a significant financial investment in the animal, Judy and Jim removed the dog from training. Judy and Jim are competitive participants in retriever field trials and the owner of Ram, a two-time National Amateur Field Champion and Field Champion Labrador retriever, not affected with EIC.

Until recently there was no test for EIC, and while veterinarians, Labrador retriever breeders, and owners of field trial dogs suspected the syndrome was becoming more common, no one knew just how prevalent it had become. Breakthrough research at the University of Minnesota College of Veterinary Medicine has changed that. Genetic researchers have pinpointed the mutant gene that causes EIC. The far-reaching discovery has vast implications, not only for the Labrador retriever population, but also for molecular research in both veterinary and human medicine.

"This extraordinary research is a great example of the strong emphasis the College of Veterinary Medicine places on comparative medicine," says Trevor Ames, D.V.M., dean of the veterinary college. "Discoveries of this magnitude involving naturally occurring diseases of animals can help the affected animals as well as humans with related conditions." Further study could lead to a better understanding of the processes that occur in other neurological diseases.

EIC involves a mutation in a gene critically involved in the communication between nerves within the central nervous system. "Communication between neurons occurs at synaptic junctions and involves the release of neurochemicals from the terminal of one neuron that interact with the adjacent neuron," says James R. Mickelson, Ph.D., professor of veterinary biosciences at the University of Minnesota and one of the lead researchers. "This synaptic communication requires structures called ‘synaptic vesicles’ to contain necessary neurotransmitters. The gene involved with EIC is responsible for making new synaptic vesicles and enabling nerve communication to continue. A naturally occurring mutation in this gene has not been identified (in any mammal, including humans) until now."

Mickelson was one of several researchers to publish the breakthrough discovery, "A Canine Dynamin 1 Mutation is Highly Associated with the Syndrome of Exercise-Induced Collapse," in the October 2008 issue of the journal Nature Genetics. Others in the College of Veterinary Medicine’s research team were: Edward "Ned" E. Patterson, D.V.M, Ph.D., internal medicine specialist; Katie M. Minor, B.A., R.N., junior scientist; Anna V. Tchernatynskaia, M.S., junior scientist; and Kari J. Ekenstedt, D.V.M., post-doctoral fellow. Susan M. Taylor, D.V.M., internal medicine specialist at the Western College of Veterinary Medicine at the University of Saskatchewan, and G. Diane Shelton, D.V.M, Ph.D., professor of pathology at the University of California San Diego School of Medicine, are also authors of the findings.

Not only did the genetic researchers identify the gene involved in EIC, they also developed and submitted a patent application for a genetic test that can identify affected dogs and carriers of the disease. The $65 test is available exclusively through the University of Minnesota Veterinary Diagnostic Laboratory. The test is welcome news because the Labrador retriever is the most common dog breed in the world. The American Kennel Club (AKC) alone issues more than 120,000 new registrations for Labrador retrievers each year. "Basically, there is no treatment for EIC, so the test will allow Labrador retriever breeders to make knowledgeable decisions to reduce the prevalence of EIC in the breed," says Christine Haakenson, Ph.D., director of research program development at the AKC Canine Health Foundation, which sponsored the latest round of research.

While many Labrador retrievers are genetically susceptible to EIC, some may never exhibit signs of the disease because they typically don’t reach the level of exercise that hunting and field trial dogs achieve. "It takes 5 to 10 minutes of very strenuous exercise before the first clinical signs appear," says Patterson. "If you stop dogs right away when they first become wobbly on their back legs, and you rest them, they’ll be fine. But sometimes, if dogs are not stopped, it affects their front legs, and later maybe their breathing—we are not certain. In severe episodes, a dog can die." Dogs gripped in an episode of EIC continue to try to perform, dragging themselves along in pursuit of their goal. They do not exhibit pain and their temperatures, while elevated, are no higher than normal dogs exercising at a similar level.

Shelton was the first to describe the disease. She first saw Labrador retrievers affected with EIC in 1990, and presented the condition to the veterinary community three years later. Shelton and Taylor began investigating EIC, analyzing owner questionnaires and evaluating affected dogs in an attempt to determine the root of the problem: muscular, cardiovascular, or neurological. They compared symptomatic dogs with asymptomatic dogs during and after strenuous exercise, but found that clinically, both populations are identical: their blood is normal, their hearts and lungs are normal, and their muscle pathology is normal. Suspecting the syndrome had a genetic basis, Shelton and Taylor turned to the University of Minnesota researchers in 2001.

The Breakthrough

"We had previously found a mutation in a mixed population of dogs that causes a primary high temperature problem called ‘malignant hyperthermia.’ EIC looked different to us, but we thought we should explore whether the two conditions were the same," says Patterson. "We suspected EIC was an inherited condition and that it might be inherited by a single gene based on the pedigrees." That led researchers from the University of Minnesota and the University of Saskatchewan to solicit blood samples and pedigrees for the genetic research.

After ruling out any connection with malignant hyperthermia, the genetic research team still had to isolate which of the 20,000 or so genes might be responsible for the syndrome by testing genetic markers spread throughout the dog’s chromosomes. Mickelson likes to think of DNA markers as flags and chromosomes as linear filing cabinets that contain genes. "We look at flags all along the chromosomes," he says. "If we see a colored flag at one position on a chromosome that all of the affected dogs have, and it is a different colored flag than what the normal dogs have, the location of that flag tells us what genes might be involved in causing the condition." Five years after beginning their work, the research team in the fall of 2006 found a linked marker in a small area of one chromosome, with 10 or so genes nearby. Within eight months of narrowing the area down, the team isolated the responsible gene: dynamin 1.

The Prevalence

Their next step was to determine how prevalent EIC was in the breed. To do that, Minor traveled to field trials in Minnesota, Wisconsin, and the Dakotas, and Taylor traveled to trials in Western and Central Canada throughout the summer of 2007, collecting DNA samples from the cheek of nearly every dog enrolled in the competitive events. "We went to seven field trials in the area and we swabbed almost every dog there," says Minor. "We also sent swabs to a national show dog competition, where DNA was collected from 200 conformation dogs." The group also tested dogs that exhibited signs of EIC that were seen at veterinary hospitals.

"That’s when we started getting a really strong idea of the frequency of this mutant gene in Labrador retrievers," says Mickelson. The group’s estimate is that 3 to 5 percent of all Labrador retrievers are affected and carry two copies of the mutant dynamin 1 gene. Another 30 percent are carriers with just one bad gene. "That’s true of field trial and hunting dogs, and show dogs, as well as pets," Mickelson adds. The team also found EIC-affected Labrador retrievers from Europe, the Middle East, and Australia. "EIC occasionally occurs in Labrador retriever crosses, and in two other retriever breeds that are closely related to the Labrador retriever: the Chesapeake Bay retriever and the curly coated retriever," he says.

Now that a test is available to identify carrier and affected dogs, breeders will be able to breed dogs in such a way that no offspring receive two mutated genes. Rankin, a Grand Hunting Retriever Champion and a Super Retriever Series winner, carries two copies of the mutant gene, but unlike many dogs affected with EIC, she is able to compete. Her clinical signs appear only during play. Rankin’s puppies could have brought her owners, Beverly and Dave Garcia, Duluth, Ga., thousands of dollars. Puppies of champion dogs can sell for as much as $5,000, and a trained dog can cost as much as $30,000.

"We were going to breed her," says Beverly. Three to four weeks before the breeding date, however, the Garcias heard that Minor was at the 2007 summer field trials testing dogs. They couldn’t attend the trials, but they called Minor and arranged to send a sample of Rankin’s blood for testing. "When the test came back that she was affected, not just a carrier, we made the personal decision to have her fixed and not breed her," notes Beverly. "We made the decision not to take the money and run."

In the future, Dave and Beverly Garcia and Jim and Judy Powers have decided that before breeding a dog they will test it for EIC. They also plan to test any puppy they buy. "Most breeders and buyers will want the test done," says Beverly. "The ethical person will want to give a guarantee to the buyer of the puppy that it is not an affected dog."

This work was funded by AKC Canine Health Foundation Grant 352.

Scientific publications:

Patterson, E.E., et al., A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Nat Genet, 2008. 40(10): p. 1235-1239.

Taylor, S.M., et al., Exercise-Induced Collapse of Labrador Retrievers: Survey Results and Preliminary Investigation of Heritability. J Am Anim Hosp Assoc, 2008. 44(6): p. 295-301.

Taylor, S.M., et al., Evaluations of Labrador Retrievers With Exercise-Induced Collapse, Including Response to a Standardized Strenuous Exercise Protocol. J Am Anim Hosp Assoc, 2009. 45(1): p. 3-13.

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