NIH Press Release
National Cancer Institute
National Eye Institute

Thursday, September 18, 1997
4:00 PM Eastern Time

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NEI Information Office
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Researchers Find First Gene Linked to Leading Cause of Blindness

A team of researchers reports this week in Science that it has found the first gene involved in age-related macular degeneration (AMD), the leading cause of blindness in older Americans.* Scientists say the gene, altered in 16 percent of people with AMD, could one day lead to gene tests that identify people who are susceptible to the disease.

The researchers say their finding is particularly interesting because the gene is altered in a variety of people with AMD, not only in individuals with family histories of the disease. Currently, most disease genes are found through family studies, making it difficult to extrapolate the findings to people who don't have a family history of a disease.

Michael Dean, Ph.D., an author on the paper and a scientist at the National Cancer Institute (NCI), said the gene could also eventually yield important clues on the causes of AMD, one of the most complex and poorly understood of all eye diseases. "As the first gene, it tells researchers where to look in retinal cells to track the disease," said Dean, whose laboratory collaborated closely with Baylor College of Medicine, University of Utah, and Harvard Medical School. "Hopefully, this information also will lead to new strategies to treat or prevent AMD."

According to the National Eye Institute (NEI), which in part supported this study, about 11 million people worldwide are potentially at risk for AMD. It is most common in people age 75 and older, affecting an estimated 30 percent to 40 percent of those in this age group, one of the fastest growing segments of the U.S. population. It is estimated that AMD already has caused visual impairment in 1.7 million Americans over age 65.

AMD occurs in the macula, the part of the eye's retina that is used to read and see straight ahead, which is called central vision. It typically occurs as the "dry" form of the disease, in which light-sensitive cells within the macula in one or both eyes gradually deteriorate and slowly erode central vision.

Most people with dry AMD don't completely lose their vision and remain fully independent until the end of their lives. However, about 10 percent to 20 percent of those with AMD develop the more serious "wet" form. It occurs when fragile, new blood vessels grow at the back of the retina, perhaps in response to the degeneration of the macula. As these blood vessels grow, they leak fluid behind the macula and interfere with its function, significantly decreasing vision.

AMD remains largely an untreatable disease, particularly the "dry" form. Laser surgery can destroy the leaking blood vessels that arise in "wet" AMD. But laser surgery can be used in only about 5 percent to 15 percent of patients and afterwards fragile blood vessels often reappear.

This week's finding stems from an earlier report that Dean described at the time as "serendipitous." While searching for new genes that might be involved in resistance to cancer drugs, Dean and other researchers in his laboratory happened upon the gene for the most common form of childhood macular degeneration, Stargardt disease. This finding was published last March in Nature Genetics.

But that finding raised an obvious question. Was the Stargardt gene, called ABCR, also altered in people with AMD? "It was a reasonable question to ask because there are similarities between the diseases," said Rando Allikmets, Ph.D., an NCI scientist and lead author on the paper. "Both cause a build up of cellular debris behind the retina and a progressive deterioration of the area near the macula."

So, Allikmets and his colleagues took the next step and looked for alterations in the Stargardt gene in blood samples from 167 unrelated people diagnosed with AMD. Eighty percent of the patients had dry AMD; 20 percent had the wet form.

As reported in Science, the hypothesis was correct. The researchers found alterations, or misspellings, in the ABCR genes of 26 patients (16 percent), half of whom did not have a family history of the disease. Notably, all but one had dry AMD.

Because a disease-causing gene may contain hundreds of possible mutations, researchers are especially interested in finding common mutations that are more likely to be present in people with a disease. Allikmets et al. report finding two: One alteration, D2177N, came up seven times and another, G1961E, appeared six times among the 26 patients.

However, neither of these mutations was associated with a specific pattern of macular degeneration, making it difficult to characterize the physiological effects of the mutations. "It's a very exciting finding and more work certainly will need to be done to investigate the significance of these mutations," said Carl Kupfer, M.D., director of NEI, which has plans under way to study the prevalence of ABCR gene mutations in larger cohorts of people with AMD.

The researchers also noted that three of the 13 gene alterations detected in the study had been reported previously in families with Stargardt disease. Because both copies of the ABCR gene must be mutated for Stargardt disease to occur, the researchers suspect that those who inherit changes in a single copy might be susceptible to AMD later in life. "It's just speculation," said Dean. "We haven't looked at enough people with these diseases yet to form any conclusions."

The National Cancer Institute, part of the National Institutes of Health, is the Federal government's primary agency for cancer research.

The National Eye Institute, part of the National Institutes of Health, is the Federal government's lead agency for vision research, and supports between 70 percent and 80 percent of basic and applied vision research in the United States.

*The study is titled, "Mutation of the Stargardt Disease Gene (ABCR) in Age-Related Macular Degeneration." The authors are Rando Allikmets, Noah F. Stroyer, Nanda Singh, Johanna M. Seddon, Richard Alan Lewis, Paul Bernstein, Andy Peiffer, Norman Zabriskie, Yixin Li, Amy Hutchinson, Michael Dean, James R. Lupski, Mark Leppert.