Understanding the mechanism by which IFNa treatment leads to removal of the HCV virus from an infected cell is of interest to Associate Professor Peter White.
Cerebellar Abiotrophy in Border Collies
Cerebellar Abiotrophy (CA) is a progressive brain disorder, with pups showing symptoms in their early months and becoming severely disabled within a few months.
Pups affected by CA have abnormal development of parts of the brain in purkinje cells and molecular cells, which leads to motor difficulties manifesting as ataxia. Symptoms range from severe, where the animal cannot walk, to mild where the pup will have an odd stance or gait. A donation from Terry Snow has allowed use of high-throughput genetic typing to identify a small region of 5 million bases with 40 genes, any of which could be the cause of CA (PhD student Jeremy Shearman and Honours student Paulina Kowalczyk).
Ataxia in kelpies, in which the disease is well characterised, is caused by Cerebellar Abiotrophy (CA), which is a loss of Purkinje brain cells. A small number of litters are born each year with the condition but they are not restricted to one line of closely related animals. This suggests that the defect is recessive and wide spread in the breed with perhaps as high as a few percent of dogs as carriers (have one good copy of the gene and one defective and are perfectly healthy but can pass on the defective gene to offspring). It is only when two carriers mate that a proportion of the offspring (one quarter on average) will inherit two defective copies of the gene, one from each parent and show symptoms of the disease.
CA occurs in a large number of dog breeds. The symptoms of CA in kelpies are quite variable. From animals that cannot stand to those where the condition goes almost unnoticed except for an unusual gait or instability in some circumstances. A characteristic sign is constant head bobbing while at rest. This variation in presentation has made the disease hard to track and recognise as a genetic problem because symptoms similar to CA can also result from viral infections in young pups. It is only when the cases are brought into the open and discussed that comparisons can be made and an idea of the extent of the problem can be obtained. The kelpie breeders are fortunate that the symptoms do not progressively worsen with time as they do in some other breeds. The symptoms in kelpies remains stable until illness or age reduces the animals strength and further weakens the animals coordination. Don Robertson of WA has produced a video showing the presentation of the diseases in kelpies and copies are available on DVD from the Working Kelpie Council.
CA in kelpies occurs in both working kelpies and bench kelpies. This further demonstrates how widely spread the condition is. It is a particular problem in working dogs where even mild cases can affect performance. It is distressing for any breeder to have severely affected pups that need to be destroyed.
The success of the Wilton lab in developing tests for 2 different fatal diseases in Border collies and their application to rid the breed of these inherited defects has encouraged other breeds to look at the problems in their breeds. At the request of members, the Working Kelpie Council approached our lab to help them develop a DNA test for CA in kelpies so that they can detect the carriers and avoid matings that would produce animals with ataxia, and eventually allow them to eliminate the problem from the breed.
Developing DNA tests requires application of molecular biology techniques very similar to forensics and is quite expensive to perform. Recent developments in the field have made the process much simpler than it once was. We now have the DNA sequence of all of the genes in the dog. The question is “Which of the 20,000+ genes is causing the problem?” This type of research requires several thousands of dollars funding each year for several years.
Funds raised by breed, new technology is available to short cut the disease gene discovery process but it is costly to implement. The microarray technology looks at 50,000 places spread around the dog DNA all at the same time. Each place is a Single Nucleotide Polymorphism, called a SNiP, where there are two possible choices for the DNA bases at that spot eg A or G. (The four possible bases are A, C, G and T.) Use of this technology was made possible by a donation from Terry Snow. The Working Kelpie Council and Swedich Kelpie Club continue to support the research with donations.
We tested 13 affected dogs and18 unaffected controls with SNP microarrays, and identified the regions where the affecteds are all similar but different to the controls. This should be the location of the CA disease gene. There are 40 genes in the region of interest that could be the CA gene and testing of these genes is ongoing.
A video has been made by Terry Snow about the disease and the research to educate breeders so that they can be prepared when the test is available. (A DVD copy is available through the Working Kelpie Council). 1.Shearman, JR, Lau VM, Wilton AN. Elimination of SETX, SYNE1 and ATCAY as the cause of cerebellar abiotrophy in Australian Kelpies. Animal Genetics 39: 573, 2008 IF 2.53 doi:10.1111/j.1365-2052.2008.01753.x