Glaucoma specialists undoubtedly applied the significance of DNA, not long after its discovery, to their understanding of the pathophysiology of inherited forms of glaucoma. Some 60 years later, researchers have found several glaucoma genes, developed sophisticated technologies that can speed the search for disease-related clues, and successfully tested gene therapy, said Wallace L.M. Alward, MD.

Dr Alward reviewed many of the advances in the study of the molecular genetics of glaucoma that have occurred in the past few decades and looked ahead to future developments as he presented the Robert N. Shaffer Lecture at the annual meeting of the American Academy of Ophthalmology last November.

Although he and the late Dr Shaffer shared an interest in gonioscopy, they also had a mutual passion for the genetics of glaucoma.

"In 1965, [Dr Shaffer] wrote a paper on genetics in congenital glaucomas," he said. "It was remarkably far-reaching in its outlook on genetics, and it's important to put this in perspective because this was just a decade after DNA [structure] was discovered and only three years after Watson and Crick received the Nobel Prize."

In the decades since Dr. Shaffer's paper appeared, researchers have identified 14 linked sites for primary open-angle glaucoma (POAG): GLC1A to GLC1N.

Three genes have been described at those loci. The myocilin gene is involved in many cases of juvenile-onset glaucoma but, more importantly, causes 3% to 5% of cases of POAG in adults.

A second gene, optineurin, causes autosomal dominant normal-tension glaucoma, which is a rare disease. Optineurin, however, is important because it may be involved in the process that damages the optic nerve.

The role of the third gene, WDR36, in POAG is controversial and unclear, but it remains the subject of intense study, he said. Although the discovery of these genes is significant, the clinical impact is limited.

"In total, we know the genetic origin of less than 5% of POAG," Dr. Alward said.

In addition, very little has been discovered about the genetics of angle-closure glaucoma. Investigators have found two linkages for dominant nanophthalmos and one gene for autosomal recessive nanophthalmos, which is quite rare, he said. Two known linkages for primary congenital glaucoma exist in addition to an important gene, CYP1B1.

Secondary, syndromic glaucomas

Research gains also have been made in the understanding of secondary and syndromic forms of glaucoma.

"The most exciting [and] relatively new finding in secondary glaucomas came out in 2007, and that's the LOXL1 gene," Dr Alward said. Scientists from a biopharmaceutical firm (deCODE genetics) and colleagues in Iceland and Sweden observed that two single nucleotide polymorphisms (SNPs) on the LOXL1 gene were associated strongly with exfoliation syndrome and exfoliation glaucoma. The protein encoded by the LOXL1 gene is involved in the production of elastin fibres.

More than 300,000 SNPs from patients with glaucoma and controls were analysed using high-resolution SNP chips and additional SNPs from public databases.

This finding is significant because of the exceptionally strong association with exfoliation syndrome, he said.

An individual in the highest-risk genotype would be 700 more times likely to develop the exfoliation syndrome than someone in the lowest-risk genotype. The findings have been replicated around the world, and one of the SNPs appears to be the disease-associated variation.

"It's very important for clinicians to be aware that most people who have this sequence variation do not get exfoliation syndrome. You should not run out and test all of your patients for LOXL1," he said. "If you look at the original data, there were 75 people with this sequence variation who did not have exfoliation for every one who did have exfoliation. Yet, it's a tremendously important finding and it's a substrate upon which people develop this disease, although there's a lot more for us to figure out."

Other advances include the discovery of the PAX6 gene, which is associated with aniridia, and two genes, FOXC1 and PITX2, associated with Axenfeld-Rieger syndrome. Nail-patella syndrome, which is associated with POAG, has been shown to be caused by mutations in the LMX1B gene.

Researchers also have learned more about the genetics of Peter's anomaly.

"It's an interesting 'garbage basket' disease in that all of the genes that can cause developmental glaucomas in isolated case reports have been shown to cause Peter's anomaly."