NIH Press Release
National Cancer Institute

Sunday, March 2, 1997

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Researchers Clone Gene Linked to Childhood Eye Disease

A team of researchers report in this month's Nature Genetics that it has found the first gene linked to one of the most common forms of juvenile macular degeneration, called Stargardt's disease*. The scientists say the gene now opens the door for genetic testing that should help affected families obtain a faster and more reliable diagnosis of the disease.

This month's paper also lays the groundwork for researchers to embark on the first detailed molecular studies of Stargardt's disease, one of the most poorly understood of the inherited degenerations of the retina.

By identifying the defects that trigger this disorder, the authors say scientists eventually may gain the knowledge to devise the first molecular treatments to slow or alter the course of this blinding disease. "Stargardt's disease has been a black box that has been locked up tightly since it first appeared in the medical literature in 1909," said Michael Dean, Ph.D., a scientist at the National Cancer Institute (NCI) and an author of the paper. "With the gene isolated, scientists now hold the key to look inside the box and hopefully emerge with novel strategies to protect the vision of people with the disease."

Stargardt's disease, also known as fundus flavimaculatus, affects about 25,000 Americans. It typically starts to damage reading vision in both eyes between the ages 6 and 20, often in more than one child in a family and often without any early signs of disease in the eyes.

Eventually, people with Stargardt's disease develop telltale signs of the degeneration, including yellowish flecks near the center of the retina and pigmentary changes at the back of the tissue. However, the most prominent feature of the disease is the appearance of a progressive and often blinding degeneration of the macula, the central part of the retina that provides reading vision.

Dean and colleagues report this month that, unlike traditional, needle-in-a-haystack searches for disease genes, they happened upon the Stargardt's gene following a different path of inquiry, showing the importance of serendipity in scientific discovery.

Dean said his laboratory began two years ago to search the human genome for new members of a family of genes called ABC, which encode proteins that transport a variety of molecules through cell membranes and are involved in chemotherapy resistance in some tumors. "Studies show that mutations in ABC genes are linked to several inherited diseases in people, including cystic fibrosis," said Rando Allikmets, Ph.D., lead author of the paper and a scientist at NCI's Frederick Cancer Research and Development Center. "We thought that by identifying new ABC genes, it might be possible to link them to other inherited disorders."

Dean's group noted that one of the 21 new ABC genes mapped in their laboratory came from a panel of expressed DNA clones from the retina. This led to another key discovery, in collaboration with scientists at Johns Hopkins University. The gene, called ABCR, turned out to be expressed only in the retina, suggesting that it might have a specialized job in the tissue and, when mutated, might cause an inherited disease.

With further mapping to pinpoint the exact location of the gene on chromosome 1, Dean said he and his coworkers began to think they might have stumbled upon the gene for Stargardt's disease, which had been localized to that region of the chromosome in 1992 but had never been isolated.

Their hunch proved correct. In collaboration with scientists at Baylor College of Medicine and the University of Utah, Dean's laboratory partially sequenced the ABC genes from members of 48 different families with clearly defined, recessively inherited Stargardt's disease. Recessive Stargardt's disease--meaning children must have mutations in both copies of the ABCR gene to get the disease--accounts for about 90 percent of all cases of the disorder.

Dean and colleagues report in Nature Genetics that they found 19 different mutations in the ABC genes from these families, resulting in a variety of predicted alterations in the ABCR protein product. By contrast, Dean and colleagues have found no mutations in the ABC genes of 40 unrelated people without the disease.

But when the scientists tried to find where in the multi-layered retina the ABCR protein is expressed, they noted something that at first seemed puzzling. The Stargardt's gene is copied exclusively in the rod-shaped retinal cells that generate the eye's peripheral and night vision. This is surprising because Stargardt's disease causes a loss of central vision, which is generated by the cone-shaped cells that proliferate in the macula at the center of the retina.

Dean said this finding seems to fit a current theory that Stargardt's disease originates in the rod cells just outside the macula. He speculated that the breakdown of the rod cells may eventually damage a part of the retina that is crucial in keeping the tissue healthy, called the RPE. As the RPE becomes more diseased, it may in turn cause the degeneration to spread to the nearby cone cells in the macula, leading to the characteristic loss of central vision.

One of the questions to emerge from this month's paper is whether the cloning of the Stargardt's gene has implications for age-related macular degeneration (AMD), the most common cause of blindness in older Americans?

Carl Kupfer, M.D., director of the National Eye Institute, said the isolation of the Stargardt's gene and other genes linked to inherited macular degenerations, such as Sorsby's fundus dystrophy, could have implications for AMD. He added that at the very least, the Stargardt's gene will help to explain more about how the macula works, information that could be important in understanding AMD.

"Identifying the Stargardt's gene is a significant medical discovery," noted Kupfer, whose institute is actively studying the causes of macular dengeration. "It may bring researchers closer to finding the cause of AMD, which results in serious visual disability and blindness affecting about 1.7 million older Americans."

* The study is titled, "A Photoreceptor Cell-Specific ATP-Binding Transporter Gene (ABCR) is Mutated in Recessive Stargardt Macular Dystrophy." The authors are Rando Allikmets, Nanda Singh, Hui Sun, Noah F. Shroyer, Amy Hutchinson, Abirami Chidambaram, Bernard Gerrard, Lisa Baird, Dora Stauffer, Andy Peiffer, Amir Rattner, Philip Smallwood, Yixin Li, Kent L. Anderson, Richard Alan Lewis, Jeremy Nathans, Mark Leppert, Michael Dean, and James R. Lupski.

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