Discovery could lead to treatment for cause of severe vision loss.
Discovery of the mutation in the gene known as HEMICENTIN-1 may help scientists better understand age-related macular degeneration -- AMD -- at the molecular level and could eventually lead to early detection, prevention and treatment of the disease, said the study's lead author, Dennis W. Schultz, Ph.D., research assistant professor of ophthalmology in the OHSU School of Medicine and at Casey Eye Institute and lead author on the study.
"By finding out the steps that lead to AMD, we hope we can develop better treatments in the future," Schultz said. The study was published today in the online version of journal Human Molecular Genetics.
Study co-author Michael L. Klein, M.D., professor of ophthalmology and project director of AMD-genetics program at Casey Eye Institute, agreed the findings provide strong evidence that this gene mutation is likely to be the cause of AMD in a large family studied by the investigators.
"Although this genetic mutation appears to be an uncommon cause of AMD in the general population, its discovery contributes to the understanding of basic mechanisms of AMD, and along with future discoveries of other genes, will ultimately lead to new ways of treating and preventing the disease," Klein said.
AMD is the leading cause of vision loss in older Americans, affecting between 4 percent and 5 percent of people older than 65 years. An additional 20 percent to 25 percent have early signs of the disease and are at risk for later development of AMD.
Early AMD is characterized by the accumulation of small deposits beneath the retina made up of lipids and cellular debris and known as drusen. Vision loss results from the dysfunction or death of the overlying cells in the central region of the retina, known as the macula. This results in impaired central vision, affecting reading, driving a car, distinguishing facial details, and other tasks requiring sharp central vision.
In recent years, researchers at Casey have been working to find AMD genes by studying large families with the disease. This gene was tracked to a region of 50 known genes, and 20 candidate genes were further studied before the HEMICENTIN-1 mutation was pinpointed.
"This has been a very hard nut to crack," Schultz said. "What it's going to let us do is find other genes and start giving us insights into how AMD is caused. It's getting the foot in the door."
The mutated HEMICENTIN-1 gene was found in 10 people, ranging in age from 54 to 92, from two generations of a large family whose members are scattered around the nation. Family members began losing vision in their 70s and the disease was "very typical of the type of age-related macular degeneration seen in the general population," Klein said.
A primary risk factor for AMD is age. People younger than 50 usually don't show signs of the disease, but incidence "comes up quite a bit" among those older than 85, Schultz said.
Most investigators believe there is a significant genetic component responsible for the development of AMD. However, the inheritance is complex, creating difficulties for scientists to determine the identity of responsible genes. Several genes are probably involved.
"Our group has recently localized five areas on the genome that are likely to contain genes associated with AMD," Klein said. Research is ongoing in trying to identify specific genes associated with AMD in these, as well as other, regions.
Current proven treatments for AMD include laser photocoagulation and photodynamic therapy. However, for most people with AMD, vision loss occurs even with treatment. Investigative therapies are being vigorously pursued, including new drugs that inhibit the growth of abnormal blood vessels in the macula that result in much of the vision loss from AMD.
As the population grows older, AMD incidence is expected to double by the year 2030. "People are living longer and longer, so a larger percentage of them will develop AMD. It's going to be a bigger problem," Schultz said.
The study was funded by the Foundation for Fighting Blindness, the National Eye Institute, the George and Carolyn Goodall Fund, the Frances and Monroe Jubitz Fund, and the Collins Medical Trust.