What is the true significance of the TIGR gene in glaucoma?

Issue: October 1997

Earlier this year, many news sources, including national broadcast media, crackled with the news that researchers had identified the gene for glaucoma — the TIGR gene. Unfortunately, reports such as "Scientists identify gene for open-angle glaucoma" (Pharmaceutical Business News, Feb. 26, 1997) may have raised false hopes that a big piece of the glaucoma riddle had been solved, and that perhaps a treatment for the majority of the sufferers of glaucoma was close at hand.

The media blitz quickly followed publication of a landmark glaucoma genetics study in the January issue of Science. A team of researchers largely based in Iowa detailed that mutations in the TIGR gene, a gene previously identified and located on chromosome 1q21-q31 at GLC1A, appear to cause juvenile glaucoma. The study further reported that the mutated gene was found in 2.9% of the primary open-angle glaucoma (POAG) patients in the study group, suggesting "that this gene plays a role in a portion of all open-angle glaucoma." This discovery was celebrated in an accompanying Science editorial as a "light at the end of the tunnel."

By the time the news reached the public, most discussion of the study’s details was abandoned in favor of a focus on new diagnostic and therapeutic methods that might someday result from the TIGR gene discovery. Sometimes it was not made clear just how far away "someday" might be. Some glaucoma researchers are concerned that further advances in the field, which are occurring at an increasingly rapid pace, should be covered without giving false hope to victims of glaucoma.

Tried not to oversell

Wallace L. M. Alward, MD, one of the study’s authors and professor of ophthalmology and director of the glaucoma service at the University of Iowa College of Medicine, noted that the team has never promoted the idea that a single gene might cause glaucoma. "We tried hard not to oversell this," he said. "But it’s a tremendously important discovery."

He said the TIGR discovery was made while studying juvenile POAG, which is similar to adult POAG except for age of onset and severity of pressure increases. Researchers have connected genes to less common forms of glaucoma, he said, but "the prize" has been to find a gene that causes POAG. "The importance of this gene has been that it’s the first gene ever for adult open-angle glaucoma."

Robert Ritch, MD, also a study author, and professor, clinical ophthalmology and chief of the glaucoma service at The New York Eye and Ear Infirmary, said the discovery "is a major step in the revolution of the way we look at glaucoma." However, Dr. Ritch granted that media coverage that implied this was the gene for most glaucomas was hyperbolic, but many sources covering the story, such as the New York Times, portrayed it accurately.

Janey L. Wiggs, MD, PhD, assistant professor of ophthalmology and genetics at the New England School of Medicine in Boston who recently published a study locating the gene for pigment dispersion syndrome, said the TIGR gene will probably point to a very rare glaucoma, and she is not convinced of links between the TIGR gene and adult POAG: "In fact, there is little evidence to suggest that any mutation in that TIGR gene causes adult-onset glaucoma."

Dr. Alward believes the study results speak for themselves: 2.9% of adults with POAG in the study were found to have TIGR gene mutations. He added that although linking the TIGR gene with that proportion of glaucoma sounds "pretty small, you must consider that could mean 100,000 people in the United States alone." Furthermore, because only part of the TIGR gene was examined by the test used in the study, the occurrence of glaucoma resulting from TIGR may be even more common.

Mansoor Sarfarazi, PhD, associate professor of human genetics at the University of Connecticut Health Center who recently published a study describing several mutations in the CYP1B1 gene as the main cause of primary congenital glaucoma, said TIGR "is the gene for juvenile onset primary open-angle glaucoma, which is extremely rare."

Dr. Sarfarazi also said there is "substantial evidence" of at least three other locations that have been identified for adult-onset POAG. "Because of these three locations, one would not expect that a mutation in the TIGR gene would cause those type of glaucomas," he said. "The TIGR gene is interesting and extremely useful to identify such genes and mutations, but this should not be taken as the gene for glaucoma. The TIGR gene is only a portion of even the juvenile glaucoma cases. There is another juvenile locus somewhere in the genome that nobody has found yet."

In defense of TIGR

However, other researchers think the TIGR mutation discovery deserves much of the prominence it received. University of Oregon researcher John Samples, MD, said that the discovery "is an important part of the puzzle." He also said press coverage helps raise awareness: "I wouldn’t fault them for having it on CNN, because things need to rise to prominence to keep public awareness of glaucoma. They don’t do ophthalmology a disservice."

However, Dr. Samples, director, Glaucoma Service, Casey Eye Institute, and professor of ophthalmology, Oregon Health Sciences University, said inaccurate coverage can instill false hope in patients: He recently had a patient ask to be injected with the TIGR protein.

Julia Richards, PhD, assistant research scientist in ophthalmology and assistant professor of epidemiology at the University of Michigan, agreed that it would be incorrect for people to walk away from the press coverage of the discovery "with the impression that this is the glaucoma gene and the answer to everything." However, she said, "It still is a big finding and a breakthrough warranting a lot of the attention that it got."

Dr. Richards said the TIGR gene discovery is "only the first step," but it gives researchers a biochemical pathway to refer to as they investigate other glaucoma genes and work on other forms of glaucoma. Genes have been discovered for other complicated, syndromic diseases that lead to glaucoma, Dr. Richards said, "but so far they weren’t helpful in giving us models for what was going on in POAG or the underlying causes."

Screening test?

The TIGR gene’s usefulness in developing a clinical screen also is an issue of concern. Dr. Ritch said because the exact gene was identified, a screening test can be developed. He also thinks the TIGR gene will show different mutations that will link to different degrees of juvenile glaucoma, similar to how the muscular dystrophy gene can reveal how severe that disease is in a person.

The Iowa team is now screening patients with POAG, juvenile open-angle glaucoma and a variety of other glaucomas. In those who have mutations, the family can be screened to determine who is at risk. A negative screen for mutation simply means that the patient does not have this particular variant of POAG.

The Iowa team is looking at isolated cases of people with juvenile POAG, Dr. Ritch said, in different ethnic groups and races to identify a possible TIGR gene mutation.

One of Dr. Sarfarazi’s projects is to screen juvenile onset families for the gene mutation, and he said he has confirmed a new TIGR mutation, although "it is still early."

Dr. Wiggs said her research team is looking at mutations in the gene in her population of juvenile glaucoma patients to determine if it is a major cause of the disease. She said eventually 20 or 30 genes will be identified that cause POAG, and then a screening will help identify people before they have suffered nerve damage, "but we’re a long way from that."

Dr. Richards said a general TIGR screening test may not be far in the future — but right now it is strictly used for research applications. Testing is an involved process, she said. "It’s not yet available in clinical labs, so anyone who wants the test is going to have to tie into one of the research centers."

Dr. Wiggs said identifying genes that may cause glaucoma has been "a huge breakthrough" in research, because the disease has so many causes and forms. Genetic research has simplified glaucoma detection because researchers simply can use blood samples.

The search for genes that cause glaucoma has bred a "fairly effective mix of competition and collaboration in the field," Dr. Richards said. "Things are moving into testing on a research level, which is how we’re going to move ourselves forward to the time when we can test in a clinical context."

For Your Information:

Robert Ritch, MD, can be reached at 310 East 14th Street, New York, NY 10003; (212) 673-5140; fax: (212) 420-8743.

Wallace L. M. Alward, MD, can be reached at 200 Hawkins Drive, Iowa City, IO 52242; (319) 356-2228; fax: (319) 353-7699.

Mansoor Sarfarazi, PhD, can be reached at University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-1110; (860) 679-3629; fax: (860) 679-2451.

Janey L. Wiggs, MD, PhD, can be reached at (617) 636-5485; fax: (617) 636-6126.

Julia Richards, PhD, can be reached at (313) 936-8966; fax: (313) 647-0228.

John Samples, MD, can be reached at (503) 494-7667; fax: (503) 494-4286. None of the doctors has a direct financial interest in the products mentioned in this article, nor are they a paid consultant for any companies mentioned.