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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
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
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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