November 25, 2004

Mutations Linked to Eye Disease

Moran Eye Center researchers have found gene mutations that result in retinitis pigmentosa (RP), one of the leading causes of blindness.

The discovery has raised fears that medications commonly used to treat both heart disease and glaucoma may trigger the eye disease in even those without the mutation because of similarities in what the mutations and the drugs do to the eyes.

The research, published in the online version of Human Molecular Genetics Wednesday, says each gene mutation hinders how photoreceptors (the eye's cones and rods) get rid of waste.

Photoreceptor action converting light into electrical impulses to send messages to the brain are energy-intensive and produce waste: carbon dioxide and bicarbonate. In a well-functioning system, the waste is carried away in minute amounts through tiny blood vessels and then disposed of by the body, said the study's lead author, Dr. Kang Zhang, assistant professor of ophthalmology and visual sciences at the University of Utah's Moran Eye Center and an investigator in the Human Molecular Biology and Genetics program at the U. Eccles Institute of Human Genetics.

The gene mutation inhibits that process, and the waste collects. People with a mutation who were studied had a defect in both how waste is removed and acid-and-base balance maintained. The result was photoreceptor degeneration, something that occurs with RP.

Although not everyone who has retinitis pigmentosa has a mutation, everyone with the mutation develops the eye disease, which typically shows up first as night blindness and can progress to complete loss of peripheral vision and significant amounts of central vision, Zhang said.

Finding the mutations has "taught us a lot about the mechanisms of RP," he said.

One of the three gene mutations in the study had been reported before, but Zhang said this research shows a completely different mechanism that causes blindness.

The mutation inhibits function of a protein complex made up of carbonic anhydrase 4 (CA4)Na+/Bicarbonate Co-transporter1 so that it cannot control acid-and-base balance.

When the waste is trapped instead of transported away, the photoreceptor cells begin to die and RP forms, Zhang said.

Early indications are the medications in question, the widely used carbonic anhydrase inhibitors, may create the same conditions and lead to RP. "The importance of a functional CA4 for survival of photoreceptors implies that carbonic anhydrase inhibitors, which are widely used as medications, particularly in the treatment of glaucoma, may have long-term adverse effects on vision," the study says.

That possible connection is being examined in mice, but the evidence is already clear enough to warrant extra care, Zhang said. Patients who are on those medications need their vision monitored to see that no harm is being done. And the safety of the drugs needs to be re-evaluated, he said, to be sure they're safe for vision.

While they have been popular and effective for both heart and eye disease, there are other medications that could do the same job, perhaps without that particular risk, if a link is proven, Zhang said.

What they've learned about this mutation may soon open the door to pharmaceutic intervention to counteract the effect of the gene mutations, Zhang said. Effective drugs to treat RP may not be too far off.

Currently, there is no cure for RP. But Zhang and others hope stem cells might one day be transplanted to "rescue" and reverse the effect of RP, which affects about 2 million people worldwide.

Besides Zhang, other investigators in the project were from the University of Alberta, University College of London, Universitatsaugenklinik Tubingen, and University Medical Center Nihmegen. The study was funded by the National Institutes of Health, the Foundation Fighting Blindness, the Ruth and Milton Steinback Fund, the Ronald McDonald House Charities, the Macular Vision Research Foundation, the Canadian Institutes of Health Research and the British Retinitis Pigmentosa Society.

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