About 2.4 million Americans have primary open-angle glaucoma (POAG), but half of them don’t even know it. The sight-trashing eye disorder causes no pain or other symptoms as it progresses for years to eventual blindness.

Adult-onset POAG strikes more than 67 million people worldwide, and is the second largest cause of sightlessness after cataracts. It leads to bilateral loss of vision in more than 6.7 million individuals. In the U.S., African-Americans outnumber Caucasian victims by three or four to one. POAG usually becomes evident after the age of 40, resulting in heightened intraocular pressure and optic nerve death.

That pressure in the eyeball’s anterior chamber occurs when its aqueous humor cannot drain out fast enough through the Schlemm canals into nearby veins, so it accumulates in the eyes. Gradually but surely, this pressure buildup destroys the fibers surrounding the optic nerve, which transmits visual images from the retina to the brain.

A less common but more vicious eye affliction than POAG is narrow-angle glaucoma (NAG), where some accidental blockage causes intraocular pressure to rise very high very rapidly. The difference between open-angle and narrow-angle glaucoma reflects the route taken by the fluid outflow. And clinically, NAG causes sudden pain, which signals its sufferer to head for the nearest eye doctor.

POAG knows no cause or cure, but eyedrops or surgery can slow its relentless course. Such medicinal or surgical intervention may carry its own severe side effects.

As for glaucoma’s etiology, risk factors aside from black race include advancing age, after 40, family history, diabetes, hypertension, myopia, migraine and use of corticosteroids. Now, however, a causative gene for familial POAG has been discovered.

It’s reported in today’s issue of Science, dated Feb. 8, 2002, under the title: “Adult-onset primary open-angle glaucoma caused by mutations in optineurin.” Its senior author is molecular geneticist Mansoor Sarfarazi, director of molecular ophthalmic genetics at the University of Connecticut Health Center in Farmington.

Gene Will Predict Disease In Unaware Victims

“We think this finding is significant in many different ways,” Sarfarazi told BioWorld Today. “The most important of them is the ability to identify presymptomatic individuals who have mutations in this particular OPTN gene, but do not have glaucoma’s clinical signs yet. Identification of these genes,” he continued, “would allow us to diagnose clinically these at-risk individuals, and take preventive action decades before the actual clinical manifestations surface and certainly before the optic nerve damage has occurred.”

Sarfarazi described how he and his co-authors in the U.S. and Britain discovered the OPTN gene and its optineurin protein: “This has been the result of several years of research,” he began. “The very first thing we had to do was identify a very large pedigree in which the glaucoma has been inherited through several generations. It numbered 19 affected members over three or four generations.

“We then used their DNAs to screen their entire genome every single chromosome. By genetic linkage mapping, we were able to identify the location of a putative gene on the short arm of chromosome 10, expected to be involved in the glaucoma etiology of that one particular family.

“Once we mapped that in 1997,” Sarfarazi recounted, “we concentrated on an area about 20 million nucleotides or base pairs in length. Next we had to extend our study from that one large family to many other kindreds, and about a year ago we were able to narrow the genomic neighborhood on chromosome 10 down to approximately 5 million base pairs. Then we studied a total of five genes, and the fifth gene proved to have mutations in this one particular OPTN gene not only in that one particular family, but also in nine of 54 families 16.7 percent.

“These mutations,” he pointed out, “were of two major types that we have observed so far. One single base-pair alteration caused a missense in an amino acid. In another mutation, two nucleotides were inserted inside the DNA of the patients with glaucoma, which resulted in truncation of the expressed optineurin proteins by 76 percent.

“The mutations we describe in our Science paper are mainly based on the familial glaucomas we have analyzed. However, we also looked at a small number of sporadic patients in the population. And we have been able to identify an identical risk-associated mutation or alteration in the sporadic patients as well as the familial. The last mutation we described totaled 17.8 percent of affected familial subjects and 12.1 percent of unaffected sporadic individuals.

“We were able to show,” Sarfarazi added, “that the neuroptin protein is highly expressed in the trabecular meshwork and nonpigmented ciliary epithelium of the eyeball, as well as in retina and other parts of the eyes and elsewhere in the body. We believe that this protein is secreted into the aqueous humor, through which it reaches the optic nerve. We think it acts as a protective agent for that nerve. However, if it does get any mutations, such as we’ve identified so far, we believe it’s resolved into haploinsufficiency. That is, part of the mutant gene is not active, or is reduced, as shown in cells from our patients. And over several decades of life, we believe that these reductions in the activities of these proteins will gradually diminish their neuroprotection of the optic nerve, resulting in its premature death, and blindness.”

Mice Now, Apes Soon, Then Diagnostic Kits

He noted, “So far we have not done in vivo experiments to study the way these proteins function. We have not created a transgenic glaucoma mouse, but we have fully cloned the OPTN gene in mice and are in the process right now of doing the same things in other animals, including primates. We don’t know the mutations in animals. We have to get the intact genes first, mutate them, then create the animal models of glaucoma.

“Age is another story,” Sarfarazi pointed out. “We have a different strategy for apes, in which we will look for mutations. But first we have to know their normal sequence.”

The university is in the process of applying to patent Sarfarazi’s invention, and is negotiating with a pharmaceutical company that is interested in creating a diagnostic kit, “but not a therapeutic at this point,” he observed, “because we don’t know how these genes function.”

(InSite Vision Inc., of Alameda, Calif., said Thursday it exclusively licensed worldwide rights to the Optineurin gene and its mutations from the university. The university will receive a licensing fee, and have a chance at a milestone payment and royalties).