Researchers Link Defective Gene to Leading Cause of Blindness in U.S.

Researchers have identified a gene that causes age-related macular degeneration (AMD), the leading cause of blindness in the United States.

Identification of the gene, reported today in the journal Science by researchers from Utah, Texas and Maryland, should eventually lead to the first treatments for the disorder, possibly including gene therapy, but it may produce more immediate benefits, experts said. The course of the disease is known to be accelerated by exposure to smoking, sunlight and high-cholesterol foods, and screening for the gene would identify individuals who should avoid such risky behavior.

As many as 1.5 million Americans have severely impaired vision caused by AMD and more than 10 million others are thought to be in the early stages of the disease.

The gene, called ABCR, was first identified earlier this year as the cause of Stargardt disease, a familial form of the disorder in which blindness usually develops by age 20.

Now, a team from the National Cancer Institute and the University of Utah have found that at least one in every six elderly people with macular degeneration carries a defective form of the gene.

“This exciting discovery is the first solid evidence that AMD is, at least in part, a genetic disease, contrary to the common misconception that it is purely a consequence of aging and undetectable in early life,” said Gerald J. Chader, chief scientific officer of the Foundation Fighting Blindness.

“This finding has far-reaching implications for current AMD patients and their families, as the door has been opened for the further discovery of treatments and methods of prevention,” he added.

AMD damages the macula, the center portion of the retina that enables the eye to look straight ahead and see fine detail. As people with AMD lose the ability to read small print and distinguish other visual details, they have to rely on their peripheral, or side, vision.

Approximately 80% of AMD cases are the “dry” form, which begins with white spots--formed by bits of debris called drusen--on the retina. As the drusen accumulates, it causes a slow, progressive loss of vision. This form cannot be treated with medication or surgery, but magnifying and telescopic lenses can help salvage eyesight.

The rest of the patients have the “wet” form, which is more severe. In wet AMD, abnormal blood vessels grow under the retina and uproot it. The detached retina and blood leaking from the vessels impair central vision. Laser treatment, if performed early, may stop the blood-vessel growth and minimize or delay the loss of eyesight.

Dr. Richard A. Lewis of the Baylor College of Medicine in Houston has been looking for the AMD gene since 1985. Because the disease occurs so late in life and has a complex genesis, he concentrated on Stargardt disease, which affects about 25,000 Americans. Its symptoms are virtually identical to those of the dry form of AMD, but it develops about 50 years earlier in life.

Lewis, geneticist Mark Leppert of the University of Utah and molecular geneticist Michael Dean of the National Cancer Institute’s Frederick Cancer Research and Development Center in Frederick, Md., reported in March that they had found the gene, which is called ATP-binding cassette transporter-retina or ABCR.

Although they do not yet know its precise function, they believe the protein produced from the gene carries substances across membranes in the retina, the light-sensitive portion of the eye.

Having found the gene in Stargardt patients, they then tested 167 people with AMD--96 from Utah and 71 in Boston. To their surprise, they report today in Science, they found that 26 of the patients, or 16%, had a mutation in their ABCR gene. That was “mind-blowing,” Leppert said.

Twenty-five of 134 patients with dry AMD had a mutation in the gene, compared to only one of 33 with the wet form.

The researchers now believe that individuals with two copies of the mutated ABCR gene--one from each parent--develop Stargardt disease, while those with only one copy develop age-related macular degeneration. Clearly, there are other genes or environmental agents that can cause the disease as well, Dean said.

While researchers continue to look for other causes of AMD, the new finding has sparked a variety of research. Because they found a variety of mutations of ABCR in the 26 patients, Leppert’s team is attempting to correlate the nature of the mutation with age of onset and progression of the disease.

Other researchers are attempting to produce mice with a defective version of the ABCR gene or with no ABCR gene at all, to determine its normal function.

According to Chader, preliminary gene therapy experiments in animals sponsored by the foundation have delayed retinal degeneration, suggesting that will be a useful approach in humans as well.