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Siberian Husky Vol. 10, No. 1 ■ December 2011 Genetic Complexity of Cataracts Hampers Efforts to Identify Causative Mutations W hen his 6-month-old female Siberian Husky, “Luna,” began running into furniture and stumbling down steps, owner Daniel Meunier of Cadyville, N.Y., knew it was unusual behavior for a young dog. When he looked into the puppy’s eyes, he saw a bluish-white milky film and recognized it as a sign of juvenile cataracts, a hereditary condition that affects about 6 percent of Siberian Huskies. An avid outdoorsman who enjoys skijoring and backpacking with his Huskies, Meunier took Luna to be examined by a veterinary ophthalmologist who confirmed that she had bilateral juvenile hereditary cataracts (JHC). In other words, both eyes were affected by the early-onset type of cataracts. The ophthalmologist recommended surgery to remove Luna’s lenses and replace them with artificial lenses to restore her vision. Though Meunier considered the cataract surgery costly, he wanted to do all he could to prevent Luna from going blind. A replacement prosthetic lens was surgically implanted in Luna’s left eye, but the right eye was not healthy enough to have an implant. Though the vision in the right eye was blurry, it remained functional for many years until Luna developed glaucoma. She then lost her vision in the right eye. Today, 11-year-old Luna continues to see well out of her left eye. She adores going on hikes and spending time outdoors with Meunier. Juvenile cataracts are a form of primary hereditary cataracts (HC). Two of Luna’s littermates also developed juvenile cataracts. Though cataract surgery corrects blurred vision, some owners find the cost prohibitive. Complications, such as Luna experienced in her right eye, can diminish the promise of vision. Cataracts are a leading cause of blindness in dogs and humans. Approximately 100 breeds are affected by primary hereditary forms,1 and some breeds may develop more than one form.2 The Siberian Husky Club of America (SHCA) requires Siberian Huskies to receive CERF (Canine Eye Registration Foundation) certification and be registered on the Siberian Husky Ophthalmic Registry (SHOR) in order to receive their eye clearances for CHIC (Canine Health Information Center) certification. “Fortunately, only a small percent- age of juvenile cataracts in Siberian Huskies progress to blindness,” says Sheila Morrissey, D.V.M., SHCA genetics chairwoman. Despite the large number of breeds affected with hereditary cataracts, little is known about the genetics of the condition, and only a single gene, heat shock transcription factor HSF4, has been identified as contributing to the development of cataracts in certain breeds.1 Samoyeds, Siberian Huskies, Finnish Lapphunds and Icelandic Sheepdogs are among the Northern breeds researchers are studying to learn more about the genetics of this condition. “We think hereditary cataracts in Northern breeds are genetically complex, meaning they probably result from mutations in more than one gene or an interaction between genes and the environment,” says Cathryn Mellersh, Ph.D., a researcher at the Animal Health Trust in the U.K. who has studied cataracts in dogs since 2001. “It is not a simple recessive or dominant condition.” Genetic research of cataracts in dogs benefits from knowledge about the genetics of the disease in humans. Continued on page 2 DNA Samples Needed for Cataract Research esearchers at the Animal Health Trust in the U.K. and OptiGen in Ithaca, N.Y., are requesting DNA samples of breeds affected by cataracts. Here is infor- R mation about samples that are needed. Additional information about sample types and how to submit them is available on their websites. Animal Health Trust Newmarket, Suffolk (U.K.) www.aht.org.uk/cms-display/ genetics_research.html Samples from dogs of any breed affected with bilateral cataracts, and dogs of any breed over 6 years of age that have been examined by a veterinary ophthalmologist and are clear of cataracts. Note that Australian Shepherds must be 8 years of age to receive clear status; a free DNA test is provided to Australian Shepherds affected by bilateral cataracts and that are over 8 years old and test clear of cataracts. The researachers particularly are interested in samples from Australian Shepherds and Golden Retrievers with PPSC, Miniature Schnauzers with congenital HC, and Irish Red and White Setters with HC. OptiGen Ithaca, N.Y. www.optigen.com/opt9_research.html Samples from dogs with PPSC between 1 ½ and 3 years of age of these breeds: Bernese Mountain Dog, English Springer Spaniel, Golden Retriever, Labrador Retriever and Rottweiler. Dogs with PPCO between 1 and 3 years of age of these breeds: Alaskan Malamute, Samoyed and Siberian Husky. Note: PPSC are posterior subcapsular cataracts that develop under the lens capsule, the sac-like covering of the eye. PPCO are posterior cortical cataracts in which the opacity starts in the rear center axis of the cortex. HC are hereditary cataracts. Causative Mutations continued from page 1 Inherited cataracts in people usually occur in association with metabolic diseases or as part of more complex genetic syndromes.1 There are about 39 genetic loci that have been associated with cataracts in humans, and mutations in specific genes have been identified for approximately 26 of these. Loss of Functional Vision Early cataracts may affect only a small part of the lens and not impair vision. As they mature, cataracts may cover the entire lens and cause loss of functional vision. They may develop rapidly over weeks or slowly over years and may occur in one eye before the other. The common effect of cataracts is loss of vision due to the cloudy opacity that develops in the normally clear lens of the eye. The opacity inhibits the lens from focusing light onto the retina. As the lens gets cloudier, the amount of light reaching the retina is reduced until a dog eventually becomes blind. Primary hereditary cataracts have breed-specific characteristics relating to appearance, age of onset, rate of progression and bilateral occurrence.2 The majority are presumed to have a simple autosomal recessive mode of inheritance, although current studies suggest this may not be the case in many breeds. Secondary cataracts may develop due to other hereditary eyes diseases, such as progressive retinal atrophy or glaucoma, or due to conditions such as diabetes mellitus, aging or trauma. The location of cataracts determines their ophthalmological classification. Posterior polar subcapsular cataracts (PPSC) begin developing under the lens capsule, which is the sac-like covering of the lens. These occur in dogs around 1 ½ to 3 years of age. Affected breeds include Alaskan Malamutes, Bernese Mountain Dogs, English Springer Spaniels, Golden Retrievers, Labrador Retrievers, Samoyeds, and Siberian Huskies. The genetic mutations responsible for hereditary cataract have been identified in four breeds: Australian Shepherd (HC), Boston Terrier (JHC, HC), French Bulldog (JHC, HC), and Staffordshire Bull Terrier (HC). Direct DNA tests are available to breeders and owners through the Animal Health Trust in the U.K. and VetGen in Ann Arbor, Mich. The Animal Health Trust has tested about 5,000 Staffordshire Bull Terriers since the test was introduced in 2006 and about 3,000 Australian Shepherds since 2008. Research leading to the discovery of these mutations initially relied on a candidate gene approach to identify possible mutations. Mellersh and her team studied cataracts in Staffordshire Bull Terriers, looking at 20 genes that had been identified as candidates for the development of inherited cataracts in humans. The HSF4 gene, located on chromosome 16 in people and chromosome 5 in dogs, provided an answer. “We found that Staffordshire Bull Terriers had an extra letter inserted in their gene code,” Mellersh says. “Then, we looked at Boston Terriers and found that they, too, had the same mutation in the HSF4 gene. As we studied this more, we found that some Bostons have a later onset form of cataracts not related to HSF4.” The HSF4 gene mutation relationship also did not hold up when the researchers looked at cataracts in other breeds, including Cocker Spaniels, Golden Retrievers and Miniature Schnauzers. These breeds had normal copies of the HSF4 gene. When the researchers looked at cataracts in Australian Shepherds, they found a mutation in the HSF4 gene, but instead of an extra letter, this breed had a deleted letter. “A few Aussies with cataracts do not carry the HSF4 mutation, which led us to speculate that another yet unidentified mutation in a different gene simultaneously circulates in the Aussie population and plays a role in the development of hereditary cataracts,” Mellersh says. A DNA test was developed for HC in Australian Shepherds, but as the mutation is described as a “risk factor” rather than a “causal mutation,” the DNA test does not give an absolute indication whether a dog will develop cataracts. “An Aussie with one or two copies of the mutation has a 17 times higher risk of developing cataracts than one without the mutation,” Mellersh says. “Because the mutation is dominant, only one parent of a dog with the mutation needs to carry the mutation for offspring to be affected. A dog with no copies of the mutation will not develop hereditary cataracts associated with HSF4, although there is a chance it could develop cataracts from yet an unknown mutation.” In collaborative research, Mellersh and Hannes Lohi, Ph.D., of the University of Helsinki and the Folkhälsan Research Center in Finland, are seeking the causative mutations for hereditary cataracts in Northern breeds. “We have excluded the HSF4 gene from involvement in the development of cataracts in Northern breeds,” Mellersh says. “We believe other genes are responsible.” They screened four Northern breeds — Finnish Lapphund, Icelandic Sheepdog, Samoyed and Siberian Husky — using genome scanning arrays to find regions of the genome shared among affected dogs that are different in unaffected dogs. “A suggested association was found on chromosome 7 in Samoyeds but not in the other breeds,” says Mellersh. Another researcher at the Animal Health Trust, Sally Ricketts, Ph.D., discovered a region on a different chromosome that is associated with cataracts in Siberian Huskies and 2 possibly Alaskan Malamutes and Samoyeds. Her work supports the theory that more than one gene mutation may be responsible for cataracts in Northern breeds, Mellersh says. “Our initial results indicate that several of these breeds may share associated cataract regions,” says Mellersh. “We are planning to follow this work up with more studies of these regions. DNA samples from additional dogs with hereditary cataracts will improve our chances of success.” The possibility of a DNA test for cataracts promises insightful information for breeders. “A genetic test will provide information that will enable breeders to continue breeding great bloodlines without fears of puppies inheriting cataracts,” Mellersh says. “A genetic test will provide simple results to use when they are making breeding decisions. Potentially, breeders can eliminate cataracts in two generations.” Sue Pearce-Kelling, president of OptiGen, a veterinary testing laboratory, cautions that the genetics of cataracts may not be simple in some breeds. “My suspicion is that we will find there are many causes of cataracts and that the DNA tests may be able to reduce genetic causes but not environmental causes. “For this reason, it will be even more important for breeders to continue to have their dogs’ eyes examined routinely by a veterinary ophthalmologist and for us to keep the message strong that a DNA test does not take the place of a clinical eye examination. The two tools complement each other to help ensure the healthiest outcomes.” Meunier, whose Siberian Husky, Luna, developed juvenile hereditary cataracts, says, “Though I am not a breeder, I would love to see a DNA test for cataracts in Siberian Huskies. It would help determine the likelihood of a particular breeding producing a higher incidence of cataracts. The economic impact of cataracts is substantial and the cumulative impact of surgery for cataracts can affect quality of life.” ■ Mellersh CS, McLaughlin B, Ahonen S, Pettitt L, Lohi H, Barnett KC. Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd. Veterinary Ophthalmology. 2009;12(6):372-378. 2 Mellersh CS, Pettitt L, Forman OP, Vaudin M, Barnett KC. Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Veterinary Ophthalmology. 2006;9(5): 369-378. 1 Purina appreciates the support of the Siberian Husky Club of America and particularly Sheila E. (Blanker) Morrissey, D.V.M., SHCA genetics chairwoman, in helping to identify topics for the Purina Pro Club Siberian Husky Update newsletter.