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

Grant Status: Closed

Grant Amount: $81,000
Dr. Martin L. Katz, PhD; University of Missouri, Columbia
January 1, 2007 - June 30, 2009
Breed(s): Tibetan Terrier, Polish Lowland Sheepdog, Australian Shepherd, Miniature Schnauzer
Research Program Area: Prevention

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.


Chen X, Johnson GS, Schnabel RD, Taylor JF, Johnson GC, Parker HG, Patterson EE, Katz ML, Awano T, Khan S, O�Brien DP: A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics 9:41-49, 2008. (http://www.springerlink.com/content/g31883676j05p853/fulltext.pdf) O�Brien DP and Katz ML: Neuronal ceroid lipofuscinosis in three Australian shepherd littermates. J. Vet. Internal Med. 22:472-475, 2008. (http://www3.interscience.wiley.com/cgi-bin/fulltext/120715560/PDFSTART) Katz ML, Coates JR, Cooper JJ, O�Brien DP, Jeong M, and Narfstr�m K: Retinal Pathology in a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 49:2686-2695, 2008. (http://www.iovs.org/cgi/reprint/49/6/2686) Awano T, Johnson GS, Wade CM, Katz ML, Johnson GC, Taylor JF, Perloski M, Biagi T, Long S, March PA, Olby NJ, Khan S, O�Brien DP, Lindblad-Toh K and Coates JR. Genome-wide association analysis identifies a SOD1 missense mutation in dogs with degenerative myelopathy: A spontaneous animal model for amyotrophic lateral sclerosis. Proc. Nat. Acad. Sci. USA, 106:2794-2799, 2009. (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2634802&blobtype=pdf) In Press Katz ML, Johnson GS and Dr�gem�ller C: Canine Neuronal Ceroid Lipofuscinoses. In: Mole SE, Lake BD and Goebel HH (eds.) The Neuronal Ceroid Lipofuscinoses (Batten Disease), 2nd Ed. IOS Press, London, In press, 2008. Submitted Katz ML, Farias FH, O�Brien DP, Khan S, Sanders DN, and Johnson GS: A missense mutation in canine CLN6 in an Australian Shepherd with neuronal ceroid lipofuscinosis. Submitted, 2009. Sanders DN, Farias FH, Johnson GS, et al. A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Molecular Genetics and Metabolism 2010;In Press, Corrected Proof.

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