A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs☆
Section snippets
Linkage analysis
Likely candidate regions for the disease gene in Border collies based on the conserved synteny between the dog and the human genomes and the positions of NCL genes in human were investigated systematically. In five Border collie pedigrees segregating for NCL, two-point linkage analysis between the disease and microsatellite markers neighboring the location of the canine homologue of CLN3 excluded this gene as the cause of Border collie NCL, and there was also a lack of support for linkage in
Discussion
The correlation of the homozygosity for the Q206X allele in nearly all affected animals, the heterozygous state in all known carrier animals, and the rarity in the general population (Table 1) strongly suggest that this variant in CLN5 causes NCL in Border collies. If not, it is in strong linkage disequilibrium with the causative allele. Mutations in the CLN5 gene in both humans and Border collie dogs result in a similar progression of the symptoms of the disease and also result in similar
Sample collection
Samples were collected from 96 Border collies from 11 Australian pedigrees, including 24 affected animals and 27 obligate carriers. Additional animals were also obtained for control purposes. One NCL-affected animal from Japan that was a descendent of Australian stock was also included. Diagnosis of the disease was made by observations of symptoms in conjunction with pathology demonstrating autofluorescence of accumulated lipopigment and positive staining with Sudan black, luxol-fast blue,
Acknowledgments
We thank Judy de Jong and members of the Hereditary Diseases Subcommittee of the Border Collie Club of New South Wales and the many owners, breeders, and clubs who have supported this project by contributing samples, donations, and information. Without the assistance of many vets, especially Isobelle Johnstone and Marilyn Gill, this work would not have been possible. We also thank Rosanne Taylor for information and advice. This study was funded by Australian Government ARC SPIRT Grant
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2019, Molecular Genetics and MetabolismCitation Excerpt :On the other hand, only Company C indicated a contribution from a breed (Border Collie) in which NCL associated with the CLN5:c.619 T variant has been reported [49]. In 2005, Australian investigators reported that a young-adult onset NCL in Border Collies was caused by a homozygous nonsense sequence variant in CLN5 [49]. Eleven years later, whole genome sequence analysis identified the identical homozygous CLN5 variant in Australian Cattle Dogs with NCL [43].
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2017, Neurobiology of DiseaseCitation Excerpt :These storage bodies exhibited ultrastructural features observed in other dogs with NCL (Fig. 9). An allelic discrimination assay revealed that this dog was homozygous for the CLN5 nonsense mutation previously reported in Border Collies and purebred Australian Cattle dogs (Kolicheski et al., 2016; Melville et al., 2005). Since NCL has not been previously reported in German Shepherd Dogs, this suggests that the dam of the affected dog probably had either Border Collie or Australian Cattle Dog ancestry.