Saluki Health

Reseacher's Best Friend

D. Caroline Coile, Ph.D.

First appeared in Dog World magazine and with permission of the author

The dog by your side may hold the secrets to good health.

“Almost human.” Never in the course of our canine covenant has that expression held such a profound truth. Besides sharing our lives and our loves, our dogs share most of our genes. The genome sequence of dogs and humans differs by less than two percent. It comes as no surprise that they also share many of our hereditary diseases.

Dogs improve our lives; they’ve done so for thousands of years. Now they’re improving the lives of even more people just by sharing the secrets of their DNA.

 

Annie and Kara, Batten and NCL

Seven-year-old Annie Allio has Batten Disease, the most common form of a group of disorders called Neuronal Ceroid Lipofuscinoses (or NCLs). Like other children with Batten, with time Annie will probably suffer mental impairment, seizures, vision loss, and become bedridden. At present, the disease is always fatal.

Eight-year-old Kara had NCL. Shortly after her eighth birthday, she started falling, bumping into walls, and having small seizures. Over the next few months her vision, balance, and mobility gradually worsened. When Kara suffered six seizures during one night, her family made the painful decision of euthanasia. Kara was a Tibetan Terrier.

Kara’s family also made the decision to donate her tissues for research in hopes of helping not only other dogs, but children like Annie. Researchers hope that data from dogs like Kara, which have a Batten-like disease, will eventually help them home in on genetic markers and perhaps, treatments. In both dogs and children the symptoms are caused by a buildup of substances called lipopigments in the cells of the brain, eye, muscle, skin, and other tissues, which eventually short-circuit the cells’ proper function and survival.

In 1995, scientists discovered a mutation in the CLN3 gene that accounts for the majority of the cases of Batten Disease in children; however, the gene doesn’t account for all forms of NCL, nor is it responsible for it in Tibetan Terriers. If the gene responsible for NCL in these dogs is found, it may lead the way to the gene responsible for these less common forms of the disease in children. “Finding dogs with diseases that are analogous to the human disorders will enable us to develop a better understanding of disease mechanisms and to test therapies that can then be applied to humans,” says Dr. Martin Katz, who is spearheading the research at University of Missouri—Columbia.

Research goes both ways. Although the goal is to find a gene responsible for a disorder in both dogs and humans, those that are only found in dogs are still worthy prizes. With them dogs can be tested for these genetic diseases before being bred. “On the basis of the human data, we can screen symptomatic dogs for mutations in the corresponding canine genes,” says Katz. “Thus, human research has helped to narrow down the genes we need to look at to find the mutations responsible for the canine diseases.”

That’s why it’s vital for researchers, dog owners, and parents of affected children to collaborate. Seeing this need, Stuart Eckmann, of the Tibetan Terrier Club of America, contacted the Batten Disease Support and Research Association in what was to become the start of a mutually beneficial relationship. Parents had a lot of practical experience to share with dog owners, much of it enlightening about the nature of the disease. For example, Tibetan Terrier owners had wondered about an unusual head tilt affected dogs had from time to time. Seeing a video of it, a parent of a Batten child identified it as a mini-seizure. The same thing happened when describing an intermittent “deer in the headlights” look of affected dogs. Parents related their children did something similar and were hallucinating at the time.

One of the most vital pieces of advice from parents concerned the often awkward chore of soliciting tissue donations from recently deceased dogs. The only way to confirm a diagnosis of the disease in dogs in through necropsy, and without confirmation, the DNA results can’t be used.  “I asked some of the Batten parents how they handled it,” recalls Eckmann, who collaborates with Katz on the project, “and their responses helped put things in perspective. They said that they handled this like organ donation. They said that they just made some advance directives that addressed this, and that they had to do it for the next generation. Listening to these parents made it easier for me to approach the subject with the Tibetan Terrier parents.” 

The strategy has worked. “We have confirmed the diagnosis of NCL from tissues of 32 Tibetan Terriers,” says Katz. “We have DNA samples from hundreds of other Tibetan Terriers.” Although Tibetan Terriers are the focus of this project, other laboratories throughout the world are investigating hereditary canine diseases with human parallels. Katz, too, is seeking more samples from other dogs. “We would like blood samples from dogs of any breed that have neurological diseases of unknown cause and that appear to have a hereditary component; that is, in which similar symptoms occur in related dogs.” For more information go to http://www.caninegeneticdiseases.net/.

 

Success Stories

With the completion of the canine genome map, human and canine genetic parallels have led to unprecedented successes. One of the most exciting began with the discovery that congenital stationary night blindness in Briard dogs and Leber’s congenital amaurosis in humans is caused by the same anomaly in the RPE85 gene. Dr. Gregory Acland and his fellow researchers at Cornell University’s James A. Baker Institute for Animal Health injected a virus carrying the normal gene into affected puppies’ retinas. The procedure restored their vision, not only making it the first successful gene therapy in a large animal, but giving hope that similar therapy could soon work for babies. 

Many dog breeds suffer from progressive retinal atrophy, a family of retinal diseases that share similar clinical features but are in fact caused by a host of distinct genetic anomalies. The same is true of the family of retinal diseases in humans known as retinitis pigmentosa. A common form of retinitis pigmentosa in humans is sex linked, that is, carried on the X chromosome. Researchers found one of the two same genes, XLPRA1, responsible for the condition in people to cause sex-linked PRA in both Siberian huskies and Samoyeds. Another unusual form of retinitis pigmentosa is dominantly inherited. Several years ago Mastiff breeders reported a type of dominantly inherited PRA. Researchers found the disease was similar in the two species and traced the gene mutation to the same region of the human and canine genomes. Yet another of the more common forms of human retinitis pigmentosa, RP17, has a canine counterpart in progressive rod-cone degeneration (prcd), which is found in at least five dog breeds. In fact, most of the 60 or so breeds that develop PRA are suspected of having the prcd version. 

Narcoleptic Doberman Pinschers led researchers to a mutation in the HCRT2 gene. This gene was found to affect a certain protein neuropeptide called hypocretin, leading researchers to find that hypocretin deficiency is associated with most cases of narcolepsy in humans. In fact, hypocretin might be important in regulating sleep, metabolic rate, and even appetite and mood in humans.

Most successes are still works in progress. University of Missouri researchers mapped the gene responsible for progressive neuronal abiotrophy (PNA) in Kerry Blue Terriers and Chinese Crested Dogs to a small segment on canine chromosome 1, which corresponds to the bottom of human chromosome 6. The PARK2 gene resides in this region, and mutations in it cause a hereditary form of Parkinson’s disease. The immobility, frozen postures, and tendency to fall that dogs with PNA exhibit are very similar to Parkinson’s symptoms. Could canine PNA be similar to human Parkinson’s? There’s still an immense amount of work to do before that question can be answered. PARK2 is the third largest gene known; trying to decipher whether it holds the mutation responsible for PNA will be a daunting task. If it does prove to be the same gene, therapies for both affected dogs and people will be much closer to reality.

Lafora's disease strikes teenagers, beginning with seizures that increase in frequency until they cause death, usually within five years. Although one gene had been identified, it wasn't responsible for all cases of Lafora. Drs. Berge Minassian, Hannes Lohi, and other colleagues at the Hospital for Sick Children in Toronto speculated that the Lafora-like syndrome seen in certain dog breeds, particularly some families of miniature Wirehaired Dachshunds, could lead to a model. These dogs had seizures with brief, jerky movements of groups of muscles (myoclonic seizures). Teaming with veterinary neurologists, they found that these affected dogs had two copies of a gene in which the base pairs are repeated, a phenomenon that has been implicated in other neurological diseases. The discovery led to a test for breeders to identify carriers and was also used to help map the alternate Lafora gene in humans. Minassian's group recently identified Lafora's disease caused by a separate gene in Beagles. They need more Beagles with this form of epilepsy to help them find this third Lafora disease gene. Minassian, who can be reached at bminass@sickkids.ca, is keenly interested in dog pedigrees with epilepsy of any kind, as, in Minassian's words, his research group considers the dog “man's best friend in identifying the elusive genes responsible for human epilepsies.”

 

Canines, Cancer, and Candidates

Dogs share not only our DNA, but our lifestyles, including the same environmental forces that interact with our genes to make us susceptible to some cancers. They develop the same types of cancers we do, but with different predispositions depending on breed. That difference, coupled with the fact that selection has created breeds with much less genetic variation within them compared to people, is one thing that makes genetic research with dogs so rewarding. When disease-affected dogs all have a certain genetic sequence that normal dogs of the same breed don’t, it focuses the attention onto that area as a candidate gene for the disease. That’s what happened when researchers studied a large family of German Shepherds in which a type of kidney cancer called hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) appeared. They were able to locate a gene responsible for kidney cancer on canine chromosome 5. A gene in the comparable region of the human genome also turned out to be implicated in human kidney cancer. 

Genetic research comparing dog and human hereditary disorders is on the fast track. But it’s still held back by lack of communication. Veterinarians and owners must report a disease or nobody will know it’s there. Breed clubs and health foundations must record incidences and make the problem known in the scientific community. Owners must be willing to share information and samples. Losing a loved one prematurely is a terrible thing. The only thing that makes it worse is if it doesn’t count for anything.

Copyright © 2007 Saluki Club of America.