A Canine DNA Bank Provides Clues to Treating a Neurological Disease

Dogs are more than just human's best friend. At the University of Missouri, Tibetan Terriers are contributing to a canine DNA bank in an on-going research program studying the genetic bases of a neurological disease that affects both dogs and humans.

The disease is known as neuronal ceroid lipofuscinosis (NCL) in dogs, and Batten disease in humans.

NCL diseases are inherited neurological disorders that have no cure. Though rare, children of parents who are carriers each have a one in four chance of inheriting the terminal disease.

In order to better understand the pathology of the disease and develop therapies, Dr. Martin Katz, professor of ophthalmology with dual appointments in the School of Medicine and the College of Veterinary Medicine, is looking to the Tibetan Terriers for help.

"The purebred dog population provides an ideal model for genetic research," said Wayne Ferguson, president of the American Kennel Club Canine Health Foundation. "The dogs' pedigrees provide detailed multigenerational relationship information. The shorter lifespan of a dog allows researchers to compress studies that would take much longer with people."

Dr. Katz is searching for the genetic bases of the disease by studying the large pool of DNA provided by the dogs' owners. The normal canine genome, which has been sequenced, is compared to the DNA of the affected and unaffected Tibetan Terriers to pinpoint the NCL mutation in this breed. Dr. Katz said in order for genetic mapping to be successful, information about the disease status of the dogs and their pedigrees must be accurate. Because of the excellent record-keeping by breed registries and close observations of their dogs by owners, registered purebred dogs are ideal subjects for genetic studies.

Using the "candidate gene" approach, Dr. Katz sequenced, or identified, the genes of affected Tibetan Terriers in specific areas thought to be comparable to those where human markers associated with the condition have been identified. Using this approach, he was able to eliminate mutations in known NCL genes as the cause of the Tibetan Terrier disease.

The next step is the identification of the NCL mutation in Tibetan Terriers. This requires that the mutant gene be located through a process called mapping or linkage analysis. This analysis involves detailed comparison of the DNA from a large number of affected dogs with the DNA of their parents and affected littermates.

"The organization of genes in a genome is like the organization of books in a library," Dr. Katz said. "Genes are arranged in a specific order on a number of different chromosomes, much like books are placed in specific orders on specific shelves in a library. Determining the precise location of a disease-causing mutation within the genome will identify the disease gene, just as going to a specific location on a specific shelf in a library will result in a particular book being located."

Once the NCL mutation in Tibetan Terriers has been identified, a simple test for the mutation can be performed on any dog using DNA extracted from a blood sample. This will enable breeders to screen dogs prior to breeding to prevent generating affected dogs in the future. Identification of the Tibetan Terrier NCL mutation also will make it possible to determine whether any humans with NCL have the mutations in the corresponding human gene.

According to Dr. Katz, human NCL often goes misdiagnosed because the disease is rare and early symptoms overlap those of other disorders. Eventually, affected children develop an array of symptoms that include blindness, seizures, cognitive decline, and loss of motor function. Often, it is not until these symptoms are well advanced that a correct diagnosis is made.

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