927: Gene Discovery in Hereditary Cerebellar Abiotrophy of Scottish Terriers

Grant Status: Closed

Grant Amount: $54,810
Natasha J Olby, VetMB PhD; North Carolina State University
January 1, 2008 - June 30, 2012

Sponsor(s): French Bulldog Club of America, Pug Dog Club of America, Inc., Sally Z. Monroe, MD FUND

Breed(s): Scottish Terrier
Research Program Area: Neurology
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Project Summary

This study has not identified the definitive mutation underlying Cerebellar Abiotrophy in Scottish Terriers as yet, but has identified a small, highly associated region. To date we have provided a detailed description of the clinical signs and diagnostic findings of this disease that has been published in one of the top veterinary journals. We have described the unique histopathological findings in detail and this work has recently been published in the top veterinary pathology journal. This pathological work has highlighted the accumulation of a type of inclusion (the polyglucosan body) in this disease, and is the first work on dogs with cerebellar neurodegeneration in which there has been a detailed mapping of neuronal loss. As such, we hope that it will provide a basis for performing such analyses in different breeds to allow objective comparisons to be made between breeds. In addition, we developed a magnetic resonance imaging (MRI) index of cerebellar atrophy that can be applied to different breeds of dog with cerebellar abiotrophy to allow a definitive diagnosis to be made antemortem. This paper has been published in Veterinary Radiology and Ultrasound. With the help of the breed society, we have collected DNA in a large number of affected and normal dogs and have used this to perform both a linkage and association analysis (the association analysis was performed with the help of an NIH collaborator at no cost to the grant). In our initial linkage analysis, we were not able to identify any region with significant linkage, which was disconcerting. However, the association analysis, performed using the new Illumina SNP chips, allowed much better coverage of the genome and did identify a region. We subsequently went back to our linkage analysis and added additional microsatellites to cover this region and confirmed that it showed significant linkage to the disease. As both of these types of different analyses have identified the same region, we have confidence in the integrity of these findings. Our next step was to identify candidate genes in the linked region for sequencing, but the region is very gene rich, containing nearly 100 genes with no single clear candidate. Therefore, in the last phase of our research we have used new sequencing technology to sequence this entire region in 6 dogs, as well as an additional region that had a less significant association. We have analyzed the sequence data that we generated and have identified over 60 variants that segregate with the phenotype (affected dogs differ from the normal dogs). We have sequenced these variants in a larger number of dogs and none of them segregated with phenotype. This work represented the end of the study, but we are continuing to work on the problem with the support of Dr. Andy Singleton of NIH. In his laboratory, we are now performing RNA seq, a technique that allows us to sequence and quantitate all expressed genes in the region. We have completed more work than anticipated during the course of this project, and regret that this has not identified the mutation specifically as yet. We are hopeful that the ongoing work we are performing will yield the answer. We are extremely grateful for the support given by AKC CHF, the STCA and all the Scottish Terrier owners and breeders who have been willing to send us clinical information and DNA from their dogs.


Urkasemsin, G., Linder, K. E., Bell, J. S., De Lahunta, A., & Olby, N. J. (2010). Hereditary Cerebellar Degeneration in Scottish Terriers. Journal of Veterinary Internal Medicine, 24(3), 565–570. https://doi.org/10.1111/j.1939-1676.2010.0499.x
Urkasemsin, G., Linder, K. E., Bell, J. S., de Lahunta, A., & Olby, N. J. (2012). Mapping of Purkinje Neuron Loss and Polyglucosan Body Accumulation in Hereditary Cerebellar Degeneration in Scottish Terriers. Veterinary Pathology, 49(5), 852–859. https://doi.org/10.1177/0300985811412622
Urkasemsin, G., Nielsen, D. M., Singleton, A., Arepalli, S., Hernandez, D., Agler, C., & Olby, N. J. (2017). Genetics of Hereditary Ataxia in Scottish Terriers. Journal of Veterinary Internal Medicine, 31(4), 1132–1139. https://doi.org/10.1111/jvim.14738

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