732: Identification of Mutations Responsible for Hereditary Neurodegenerative Disorders in Dogs

Grant Status: Closed

Grant Amount: $81,000
Martin L. Katz, PhD; University of Missouri, Columbia
January 1, 2007 - June 30, 2009

Sponsor(s):

Breed(s): Tibetan Terrier, Polish Lowland Sheepdog, Australian Shepherd, Miniature Schnauzer
Research Program Area: Neurology
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Project Summary

Both humans and dogs suffer from a large number of inherited disorders that lead to degenerative changes of the central nervous system. These diseases can cause such symptoms as visual impairment, loss of coordination, seizures, declines in cognitive function, paralysis, and ultimately death. Among these inherited neurodegenerative disorders is the neuronal ceroid lipofuscinoses (NCLs). NCLs have been reported in a large number of dog breeds. To date, mutations in at least 8 different genes have been found to cause NCL in children. Dogs have versions of most of the genes present in humans. This research project enabled researchers to find the mutations in 5 genes that cause NCL in dogs: the CLN8 gene in English Setters, the CTSD gene in American Bulldogs, the CLN6 gene in Australian Shepherds, and the TPP1 and PPT1 genes in Dachshunds. DNA tests are currently offered for these mutations. Unfortunately, it appears that each NCL mutation is unique to a specific breed, and that in fact more than one NCL mutation can occur in the same breed. Therefore, research must be done to identify the NCL mutation for each breed in which it occurs. A primary focus of continuing research is to identify the mutations that cause as many forms of canine NCL as possible and to offer these tests at as low a cost as possible. Although this research project had a number of successes, their greatest frustration has been that they have not yet identified the mutation responsible for NCL in Tibetan Terriers. Tibetan Terriers suffer from a late-onset form of NCL in which the symptoms usually do not become apparent until the dog is more than 5 years old. During this project, have identified a region of chromosome 2 was identified on which the Tibetan Terrier NCL gene appears to be located. The location of this gene indicates that it is a gene that has not previously been associated with NCL in either dogs or humans. The researchers hope to be able to continue their work on this breed until they are able to identify the disease-causing mutation.

Publication(s)

Awano, T., Johnson, G. S., Wade, C. M., Katz, M. L., Johnson, G. C., Taylor, J. F., … Coates, J. R. (2009). Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences, 106(8), 2794–2799. https://doi.org/10.1073/pnas.0812297106
 
Chen, X., Johnson, G. S., Schnabel, R. D., Taylor, J. F., Johnson, G. C., Parker, H. G., … O’Brien, D. P. (2008). A neonatal encephalopathy with seizures in Standard Poodle Dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics, 9(1), 41–49. https://doi.org/10.1007/s10048-007-0112-2
 
Farias, F. H. G., Zeng, R., Johnson, G. S., Wininger, F. A., Taylor, J. F., Schnabel, R. D., … Katz, M. L. (2011). A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan Terriers. Neurobiology of Disease, 42(3), 468–474. https://doi.org/10.1016/j.nbd.2011.02.009
 
Katz, M. L., Coates, J. R., Cooper, J. J., O’Brien, D. P., Jeong, M., & Narfström, K. (2008). Retinal Pathology in a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis. Investigative Ophthalmology & Visual Science, 49(6), 2686. https://doi.org/10.1167/iovs.08-1712
 
Katz, M. L., Farias, F. H., Sanders, D. N., Zeng, R., Khan, S., Johnson, G. S., & O’Brien, D. P. (2011). A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis. Journal of Biomedicine and Biotechnology, 2011, 1–6. https://doi.org/10.1155/2011/198042
 
O’Brien, D. P., & Katz, M. L. (2008). Neuronal Ceroid Lipofuscinosis in 3 Australian Shepherd Littermates. Journal of Veterinary Internal Medicine, 22(2), 472–475. https://doi.org/10.1111/j.1939-1676.2008.0079.x
 
Sanders, D. N., Farias, F. H., Johnson, G. S., Chiang, V., Cook, J. R., O’Brien, D. P., … Katz, M. L. (2010). A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Molecular Genetics and Metabolism, 100(4), 349–356. https://doi.org/10.1016/j.ymgme.2010.04.009

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