960: Identification of Genes That Cause Liver Copper Toxicosis

Grant Status: Closed

Grant Amount: $70,283.58
Andrew Mason, PhD; University of Alberta
September 1, 2008 - September 30, 2013

Sponsor(s): Berner Lovers, Bernese Mountain Dog Club of America, Flat-Coated Retriever Foundation, Golden Retriever Foundation

Breed(s): Bedlington Terrier
Research Program Area: Hepatic Disease
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Project Summary

Bedlington terriers, and some other terrier breeds such as the Skye Terrier, the West Highland White Terrier and the Doberman Pinscher, develop copper storage that can lead to early death from liver disease (copper toxicosis, CT). The gene, COMMD1, was reported to be the cause of liver disease in Bedlingtons, as a deletion of the mid part of the gene was identified in some affected dogs. We also identified this deletion in our pedigrees, but proposed that this could not be the sole cause of the disease, as the deletion did not always predict the disease status of the dogs. We have collected several large pedigrees of Bedlington terriers that include both sick and healthy dogs that do not always fit the expectations according to deletion results. Currently, one third of the affected dogs in our database that have reliable biopsy data, do not carry two copies of the COMMD1 deletion. The underlying genetic cause of disease in these dogs remains unknown. This situation puts dogs at risk of ill health and could be detrimental to future Bedlington Terrier breeding plans. We performed a total genome scan on 17 dogs (affected and unaffected /control). We determined that only blood samples are reliable for testing, cheek swabs or paraffin liver samples proved unsuitable. Our genome scan has revealed five potential regions of interest, and we plan to assess these SNPs in our large sample set. In addition, we are now using pioneering new whole genome sequencing (WGS) technologies that enable almost complete sequencing of a dog genome (85-90%). WGS is now considerably less expensive than even two years ago, and is now a viable option for our study. With this approach we will be able to directly identify changes in the dog genomic sequence to identify the gene defect in dogs that have high liver copper but apparently normal COMMD1. The information generated from our WGS data will be applied to all of our collected samples, and will help us to understand: 1. whether COMMD1 is the only defective gene, 2. if there are additional changes in COMMD1 (not yet found), or 3. if a mutation in another gene may be involved. We aim to identify any additional genetic changes that lead to copper toxicosis, in the hope of eliminating copper toxicosis from the Bedlington Terrier breed. We are truly thankful for the efforts of breeders and owners who have been instrumental in gathering information and samples for this study.

Publication(s)

Coronado, V. A., Bonneville, J. A., Nazer, H., Roberts, E. A., & Cox, D. W. (2005). COMMD1 (MURR1) as a candidate in patients with copper storage disease of undefined etiology. Clinical Genetics, 68(6), 548–551. https://doi.org/10.1111/j.1399-0004.2005.00524.x
 
Coronado, Veronica A., Damaraju, D., Kohijoki, R., & Cox, D. W. (2003). New haplotypes in the Bedlington terrier indicate complexity in copper toxicosis. Mammalian Genome: Official Journal of the International Mammalian Genome Society, 14(7), 483–491. https://doi.org/10.1007/s00335-002-2255-3
 
Coronado, Veronica A., O’Neill, B., Nanji, M., & Cox, D. W. (2008). Polymorphisms in canine ATP7B: Candidate modifier of copper toxicosis in the Bedlington Terrier. The Veterinary Journal, 177(2), 293–296. https://doi.org/10.1016/j.tvjl.2007.04.012

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