Understanding retinal degeneration
To those who remark on the slow progress of science, Heritage Senior Scientist Dr. Paul Schnetkamp offers a reality check. He tells them about the phototransduction cascade, the process by which light is converted into electrical signals in specialized cells in the retina, called photoreceptors.
"When I started doing research in the late 1970s, we knew for sure about one protein involved in the phototransduction cascade. By the late 1980s, all major components of the cascade were known, with proteins identified and purified. The focus then shifted to retinal disease, where something goes wrong with phototransduction. Now 190 genes that cause retinal disease have been mapped, and 173 have been identified. Over the past six years, an average of 12 new retinal-disease genes have been mapped each year. The progress has been really quite amazing."
Understanding the genetics is important because mutations in genes are responsible for hereditary degenerative retinal diseases that cause blindness. Retinal degeneration affects more than 10 million North Americans. About 95% of these individuals have age-related macular degeneration, caused by an abnormal blood supply to the light-sensitive portion of the retina.
Dr. Schnetkamp studies a gene family by the name of NCKX, one of a small number of families that produce proteins necessary for phototransduction. The genes in this family make five proteins. Dr. Schnetkamp's research team discovered one of them, one that is found only in the rod photoreceptors; they also study another one, which is found in the cone photoreceptors and throughout the brain. (Rods, so called because of their shape, function in dim light and are used in peripheral vision. Cones function in bright light and are adapted to detect colours.)
All five of these proteins regulate the amount of calcium in cells. If they are not properly functioning, the rod or cone cells will not be able to get rid of calcium, phototransduction will stop, and vision will cease; too much calcium will eventually kill the cells. The key role these proteins play in the phototransduction process highlights the importance of this gene family in hereditary retinal diseases.
Dr. Schnetkamp has continued to study these proteins—cloning the genes, identifying their location on chromosomes, and screening patients with hereditary retinal disease to see if they have the mutations that could lead to blindness.
"My focus has now shifted away from vision to trying to understand how these proteins actually work in the body," says Dr. Schnetkamp. "This detailed understanding is absolutely necessary. It's my belief that, with one or two exceptions, retinal disease is not going to be treated effectively by drug interventions. Gene therapy has been successful in several animal models of retinal degeneration. To apply this to retinal degeneration in human patients, we'll need to know which genes to target and how they function."