Elsevier

Genomics

Volume 86, Issue 3, September 2005, Pages 287-294
Genomics

A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs

https://doi.org/10.1016/j.ygeno.2005.06.005Get rights and content

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a neurodegenerative disease found in Border collie dogs, humans, and other animals. Disease gene studies in humans and animals provided candidates for the NCL gene in Border collies. A combination of linkage analysis and comparative genomics localized the gene to CFA22 in an area syntenic to HSA13q that contains the CLN5 gene responsible for the Finnish variant of human late infantile NCL. Sequencing of CLN5 revealed a nonsense mutation (Q206X) within exon 4 that correlated with NCL in Border collies. This truncation mutation should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL. A simple test was developed to enable screening of the Border collie population for carriers so the disease can be eliminated as a problem in the breed.

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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    Sequence data from this article have been deposited with the GenBank Data Library under Accession Nos. AY885121, AY885122, and AY885123.

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