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UI researchers identify gene that causes common form of glaucoma

IOWA CITY, Iowa -- Researchers at the University of Iowa College of Medicine have identified a gene responsible for primary open angle glaucoma, the most common form of glaucoma and the second leading cause of legal blindness in the United States.

In an article published in the Jan. 31 issue of the journal Science, UI researchers, led by Drs. Edwin Stone, associate professor of ophthalmology, Val Sheffield, associate professor of pediatrics, and Wallace L. Alward, professor of ophthalmology, report that mutations in a gene located on chromosome 1 are responsible for primary open angle glaucoma. The UI team had linked this form of glaucoma to chromosome 1 in a separate study three years ago.

"These study results point to the potential availability of a blood test that can identify people at risk for primary open angle glaucoma," says Dr. Thomas Weingeist, UI professor and head of ophthalmology. "Therefore, more attention can be paid to following these patients and perhaps treating them earlier. It also means that it may be possible to identify drugs that can be more effective in treating this disease."

Glaucoma is a condition in which loss of vision is characterized by the degeneration of the optic nerve, usually associated with increased pressure within the eye. This increased pressure can be caused by problems in the eye's trabecular meshwork, which filters the watery fluid, known as the aqueous humor, that bathes the inside chamber of the eye behind the cornea and in front of the lens.

"In 1993 we studied a large family with a history of glaucoma and identified a region of chromosome 1 to be associated with juvenile open angle glaucoma, which is a subset of primary open angle glaucoma and occurs at an earlier age," Stone says. "Studies by other researchers subsequently identified additional families that mapped to this region. For this study, we used genetic linkage analysis and shared genetic information among the families to further narrow that area on chromosome 1."

Several genes that mapped to this region of chromosome 1 were considered by the UI researchers as the glaucoma-causing gene. The researchers determined that one gene in particular -- known as the TIGR gene -- existed within this region and was known to be expressed in the trabecular meshwork and ciliary body of the eye, both of which are involved in the maintenance of the intraocular pressure.

Stone, Sheffield, Alward and their colleagues studied eight families they suspected had gene mutations at this specific area on chromosome 1, including the original family that allowed UI researchers to identify chromosome 1 three years earlier. Of the eight families, the UI team found three different TIGR gene mutations among four of those families.

"At that point we could say that this gene causes a type of inherited glaucoma in families in which the disease gene can be shown to map to chromosome 1," Sheffield says. "But perhaps this is only one-tenth of one percent of all glaucoma. So, the next step was to determine if the gene was also mutated in some unrelated patients with glaucoma."

The UI team studied 227 unrelated glaucoma patients with a family history of the disease and 103 unselected, or "walk-in," primary open angle glaucoma patients seen at a single clinic. Of the 227 patients with a family history of the condition, 10 (nearly 4.5 percent) had one of the three TIGR gene mutations. Of the 103 unselected patients, 3 (about 3 percent) harbored one the three TIGR gene mutations.

"These findings suggest that this gene plays a role in a portion of all primary open angle glaucoma," Stone says. "When you consider that glaucoma affects between 2.5 and 5 million people in the United States, the 3 percent we found in the unselected patients group suggests that mutations in the TIGR gene cause glaucoma in more than 100,000 people."

The identification of the gene for primary open angle glaucoma will help researchers better understand the disease, which could lead to better treatments. "The TIGR gene is believed to cause increased pressure in the eye by obstructing the outflow of the aqueous humor, the fluid that bathes the inside of the eye," Alward says. "Now it's possible to examine whether the mutations we describe in this study play a role in this."

Identifying the TIGR gene also increases the possibility of developing accurate testing for genetic predisposition to glaucoma before symptoms arise. "Open angle glaucoma can be treated with existing drugs or surgery in most cases," Alward says. "Discovering specific glaucoma-causing mutations will make it possible to identify patients at risk for this disease before significant visual loss has occurred."

The UI study was funded through grants from the National Eye Institute of the National Institutes of Health, the Roy J. Carver Charitable Trust and the organization Research to Prevent Blindness. The UI Research Foundation is seeking patent protection for the UI team's body of research.

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