642: Investigation of the Genetic Mutations Underlying Progressive Retinal Atrophy

Grant Amount: $104,580

Simon M. Petersen-Jones, DVM, PhD; Michigan State University

July 1, 2006 - December 31, 2008

Sponsor(s): American Belgian Tervuren Club, Inc., American Chinese Crested Club, Collie Health Foundation, Italian Greyhound Club of America, Old English Sheepdog Club of America, Papillon Club of America, San Joaquin Kennel Club

Breed(s): Papillon, Collie, Old English Sheepdog, Irish Wolfhound, Italian Greyhound, Belgian Tervuren, Dachshund

Research Program Area: Ophthalmology

Project Summary

Our approach has been to identify genes that if mutated could be expected to result in a disease like PRA. Our first step was to develop markers within those genes that could be used to show if any one of those genes was associated with PRA in the breeds under investigation. Once the markers were developed we could then use them to test for possible "association" of the gene locus with PRA in each breed. With evidence to suggest PRA was recessively inherited in the breeds we would expect all affected dogs to have the same version of the marker within the gene that caused the disease. If we find that affected dogs of one breed have different versions of the marker for a particular gene it makes it unlikely that the gene is the PRA causing gene in the breed. We have investigated the genes in the following breeds: Collie (we stopped working on this when the PRA gene was discovered), Old English Sheepdog, Papillon, Tibetan terrier, Belgian Tervuren, Chinese Crested, Italian Greyhound, Irish Wolfhound and Miniature Dachshund. Although we have been able to rule out many of the genes, we have not identified the causal gene mutation in the breeds. The retina is a very complex structure and there are many different genes that function in the retina and therefore could cause PRA. The situation has been made more complex by discovery in human families with diseases similar to PRA that the disease can be caused by mutations in genes that are active in other parts of the body as well as the retina. However, when these genes do not function properly only the retina is affected. The other parts of the body probably have additional genes that can play a similar role to the mutated gene and provide enough function that the other parts of the body are not affected. Previously it was assumed to be very likely that when only the retina was affected by an inherited disease that the gene mutated to cause it only functioned in the retina. The realization that genes that also function in many other parts of the body can cause disease of the retina only has meant that we need to consider many other classes of genes that as candidates for retinal disease such as PRA. Our future direction is to take a genome-wide mapping approach to try to identify the position of the PRA gene in each breed. To do this we need sufficient DNA samples from affected dogs and their relatives. We have started this approach with the breed that we have most samples from PRA-affected dogs, the Italian Greyhound. This has enabled us to locate some areas of the genome that are of interest and work is progressing to narrow down those regions and to sequence genes with them. We are confident that this approach will yield the results we are looking for. We wish to continue to work the other breed clubs to obtain further DNA samples from affected dogs to enable us to map the PRA gene in those breeds. The collection efforts in the Papillon and Miniature Dachshund breeds are going well and we look forward to applying the new gene mapping techniques to investigate PRA in those breeds as well.

Publication(s)

None at this time.