747: The Mapping and Characterization of Mutations Responsible for Canine Glaucoma
Grant Status: Closed
The research used a state-of-the-art procedure known as a genome-wide association study (GWAS) in attempts to find the chromosomal locations of the mutations that cause canine glaucoma. A GWAS is done with a device called a SNPchip which supports the simultaneous analysis of a DNA at tens of thousands or hundreds of thousands of distinct locations spread throughout each of the canine chromosomes. The results obtained from a group of affected dogs (the "cases") are compared to the results from a group of healthy dogs that should have the same genetic background (the "controls"). In the last three years, the investigators conducted many GWAS. When the disease in most or all of the "cases" is caused by the same single mutation, they have almost always obtained large "case" versus "control" differences in SNPchip results from assays at chromosomal sites near the mutation. By analyzing the genes at these chromosomal sites the investigators can usually, but not always, find the mutation. When they have not obtain large "case" versus "control" differences in SNPchip results, they have interpreted this to mean that the disease in different individuals in the "case" group results from different mutations and/or that the disease results from a combination of mutations and perhaps also from environmental factors. In this project the investigators conducted six GWASs to find the chromosomal locations of mutations responsible for canine glaucoma. The first GWAS involved "case" and "control" DNA samples from Dandie Dinmont Terriers and was conducted in conjunction with Dr. Hannes Lohi's research group in Helsinki Finland. This study produced moderately strong evidence that appears to have localized the Dandie Dinmont Terrier glaucoma mutation to a specific chromosomal location. The project's investigators and the Finnish researchers have examined genes from within this chromosomal location; however, they still have not found the mutation responsible for the glaucoma of Dandie Dinmont Terriers. The other five GWASs involved Basset Hounds (three studies), Bouvier des Flandres, and Petit Basset Griffon Vendeens. In each study, they found only small "case" versus "control" differences in SNPchip results which could signal the chromosomal locations of glaucoma-causing mutations but more likely resulted from random variation. The third Basset Hound GWAS involved samples for "cases" and "controls" for this collected by Drs. Markus H. Kuehn, University of Iowa, and Sinisa D. Grozdanic, Iowa State University. An initial evaluation at the University of Missouri revealed a weak but possible association peak. The SNPchip data has been sent to the University of Iowa for further analysis. During this funding period, the investigators conducted a more successful GWAS in which they used Jack Russell Terrier cases and controls to discover the mutation responsible for primary lens luxation in a variety of terrier breeds. Although PLL and primary glaucoma are usually considered to be distinct diseases, this distinction is not clear cut in all cases. Furthermore, PLL can lead to secondary glaucoma and primary glaucoma can lead to secondary lens luxation. They therefore tested for the primary lens luxation mutation in DNA from all dogs in our collection that were diagnosed with primary glaucoma. Glaucomatous representatives from most breeds tested negative for the primary lens luxation mutation. Nonetheless, several Welsh Terriers that were diagnosed with primary glaucoma tested positive for the lens luxation mutation. Furthermore, they found that a Chinese Shar-Pei with a well documented case of primary glaucoma had a different mutation in this same gene. It appears that primary lens luxation and primary glaucoma can sometimes develop concurrently as a disease syndrome in the same dog.
Help Future Generations of Dogs
Participate in canine health research by providing samples or by enrolling in a clinical trial. Samples are needed from healthy dogs and dogs affected by specific diseases.