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Homing in on a Genetic Cause of Severe Glaucoma

Summary

With a new animal model of angle-closure glaucoma, researchers have pinpointed a gene that may be to blame.

More than half of the cases of blindness due to glaucoma are a result of angle-closure glaucoma (ACG), a less common but far more serious form of the disease. Until now, researchers have made little progress toward understanding the molecular cause of ACG. But Howard Hughes Medical Institute researchers have now developed an animal model of ACG that mimics the human disease and pinpointed a gene that may be implicated in this and other eye disorders.

“We’ve identified an important new gene that underlies angle-closure glaucoma phenotypes in mice, and conditions affecting ocular size in mice,” says Simon John, the HHMI investigator who led the study. “This gene is going to give us new insight into pathways for understanding these conditions, and we’re following up to understand the gene in human patients.”

There are many people whose eyes are at risk of ACG, and we might be able to intervene before the problem ever starts.

Simon W. M. John

Angle-closure glaucoma occurs when the cornea and iris of the eye meet at too narrow an angle, blocking drainage structures responsible for drawing off excess fluid. Eyes constantly produce fluid and without adequate drainage, that fluid can build up rapidly and increase internal pressure to a degree that quickly becomes dangerous. Figuring out why some people are more susceptible to the disease and what molecular pathways are responsible could ultimately lead to better treatments and predictive techniques.

“Virtually nothing is known about the molecular factors that regulate ACG and so it’s a very poorly understood glaucoma. But there are 16 million people affected by it. Our linking a novel gene to it is a key step towards understanding the molecular processes,” says Sai Nair, a postdoctoral fellow in John’s research group at The Jackson Laboratory.

In research published May 1, 2011, in the journal Nature Genetics, John, Nair, and colleagues describe a mouse mutant with eyes that mimic those of humans with ACG. Like human eyes, they begin to show dangerous intraocular pressure when the mice are still young. And like humans with ACG, the mice have eyes that are slightly smaller than their peers but lenses of normal size—a combination prone to decreased angle size.

“What’s fascinating about ACG is that there are a lot of different physiological processes interacting in complex ways, and there hasn’t been an underlying unifying mechanism identified that can explain all these changes,” says John. With their new mouse model of the disease, scientists are now better equipped to tease apart those mechanisms. John is already setting the pace, along with Nair, who is a first author of the Nature Genetics paper.

The team first observed the ACG-like symptoms in a mouse carrying an unknown gene mutation. Together with their colleagues, John and Nair mapped the mutation to a specific gene, which encodes an enzyme called a protease that’s responsible for breaking down certain proteins. Mounira Hmani-Aifa at the Université de Sfax in Tunisia, who has been studying the genetics of families with inherited eye disorders, has found that in humans, the gene is located in a region of the genome that has been linked to another vision disorder called posterior microphthalmia. Patients with posterior microphthalmia have small eyes with extreme hyperopia, or severe far-sightedness.

The protein may also be important in a process known as emmetropization, which occurs as a baby’s brain begins to process the world around him and corrects the eye’s shape until it focuses light so precisely on the retina as to create perfect vision—suggesting defects associated with ACG may begin during childhood development.

To examine the clinical relevance of their mouse studies, the John’s team collaborated Hmani-Aifa's team. They discovered that the mutations in the gene they saw in their mice are present in some patients with posterior microophthalmia. Nair adds that the team has established a new collaboration with Tin Aung and Eranga Vithana of the Singapore Eye Research Institute to screen patients with ACG to determine whether there is an association between the gene and the disease in humans.

Now that a new gene has been implicated and a mouse model developed, John plans to go even further. “Our ultimate hope is that we can define these pathways well, and it can lead to novel therapeutic interventions, or even interventions that would lower risk without surgery,” he says. “There are many people whose eyes are at risk of ACG, and we might be able to intervene before the problem ever starts.”

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Investigator
The Jackson Laboratory
Genetics, Neuroscience

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