By David N. Leff

Glaucoma is not life-threatening; it's sight-threatening. It causes no pain, displays no symptoms, offers no advance warning of its stealthy, incurable savaging of vision.

"More than 15 million North Americans may have some form of glaucoma," wrote molecular endocrinologist Vincent Raymond in the February 1997 The American Journal of Human Genetics, "but at least half of them may not be aware of it."

In an editorial on "The molecular genetics of glaucoma," Raymond cited a recent World Health Organization estimate that more than 5 million people in the world are blind as a result of glaucoma. In the U.S., African-Americans outnumber Caucasian victims by three or four to one.

Today's issue of Science, dated Jan. 31, 1997, reports discovery of the first gene responsible for one major form of the multiform eye abnormalities lumped under the glaucoma rubric. The paper's title: "Identification of a gene that causes primary open angle glaucoma." Its senior author is medical and molecular geneticist Val Sheffield, at the University of Iowa College of Medicine, in Iowa City.

"Glaucoma," Sheffield told BioWorld Today, "refers to several different diseases. Its most common form," he continued, is something called Primary Open Angle Glaucoma (POAG). That's the type that usually occurs after the age of 40, and results in increased optical pressure and optic nerve death." POAG, he added, "probably accounts for 70 to 80 percent of all glaucomas."

No Symptoms — Except Going Blind

Among the remaining percentage, he cited congenital glaucoma, in which babies are born with eye abnormalities leading to increased pressure inside the eyeball, and certain rare conditions, such as Rieger's syndrome, where the glaucomatous eyes are only one of several disease states.

"So with POAG," Sheffield observed, "you have a disease that has no symptoms — except people going blind — but that's treatable, if you can diagnose it. That makes glaucoma a little bit different from such genetic diseases as Huntington's and Alzheimer's, because there's no therapy for those.

"The insidious loss of vision is so gradual," he pointed out, "that people don't realize they're losing their sight. So by the time they go to the eye doctor, they've lost a substantial portion of their vision, and it's irreversible."

He pointed out, "There are very successful glaucoma treatments, with early diagnosis. Eye-drop medications can lower the optic pressure, and if this fails, surgery can implant a stent or cannula into the trabecular meshwork, to maintain free flow of the intraocular fluid."

The trabecular meshwork cells, he explained, "are in a region of the eye involved in regulating intraocular pressure. The protein product of the gene we describe in Science is expressed in those cells."

The human eyeball can be compared to a self-sealing automobile tire. The normal pressure on the aqueous and humoral fluids in the globe's anterior and posterior chambers is like an inflated tire. It keeps the globe of the eye inflated and fluid-sealed, so it doesn't collapse."

Abnormally high intraocular pressure is one hallmark of glaucoma. The other is death of the optic nerves, which transmit the retina's visual images to the brain.

"We don't know," Sheffield said, "whether that rise in pressure causes optic nerve death. There's not even a really good hypothesis as to why that happens. What we do know is that the high pressure and nerve death are often associated."

That blinding demise of the nerves is not sudden. It may take years after the ophthalmologist first records a rise in a patient's intraocular pressure. Frequently, the first sign is cupping, a small depression in the optic disk, the nerve's interface with the retina.

In 1993, Sheffield and his co-workers announced that they had located a gene for POAG on the long arm of human chromosome 1. Since then, they have been closing in on this genomic region, and finally, by classical gene mapping and linkage analysis of glaucoma families * reported in today's Science * were able to pinpoint, isolate and sequence the gene's coding region. It spans 1,491 base pairs, which encode that 497-amino-acid protein involved in maintaining the eye's proper pressure.

Mutations in this gene, Sheffield said, account for the glaucomatous aberrations in the pressure, and presumably — guilt by association — for the optic nerves' death, and consequent blindness.

As for the normal, unmutated gene's function, "We don't know much about that," he said.

"We're currently working on the rest of the gene sequence, the intronic sequences, promoter, and so on, as well as studying the gene and its product, to see where and when the protein is expressed."

Sheffield also is propagating mouse models, based on mutating the gene. This work in progress, he observed, "points to the possibility of screening people who are at risk of glaucoma, to identify those at greatest risk, and making sure they go to the eye doctor."

Outlook: Screening, Therapeutics, More Genes

Such a molecular screen, he went on, "would look at this gene in people to see if there are any mutations, and so identify those at high risk of developing the disease. They would be followed closely for the first indication of increased ocular pressure, for which they would receive medical treatment.

Beyond that initial diagnostic application lies a therapeutic potential: "Once we know more about the gene itself, and what its product does, that may very well suggest new therapies.

"If for example we discover that the reason these mutations cause glaucoma is that this abnormal protein builds up in the trabecular meshwork , there may be a medication applied to the eye to inhibit that pressure build-up."

Sheffield concluded: "POAG is not a single disease. Having found the first gene that causes it opens up one other exciting avenue of research — going after additional glaucoma genes." *