University of Utah study suggests cellular waste to blame for a form of blinding eye disease

Discovery offers hope for a pharmaceutical intervention to treat some forms of retinitis pigmentosa

Gene mutations that impair the ability of photoreceptor cells to properly dispose of waste – and as a result cause the blinding eye disease retinitis pigmentosa – have been identified by vision researchers at the University of Utah’s Moran Eye Center. The discovery raises concerns that carbonic anhydrase inhibitors (medications often used to treat both heart and eye diseases) may adversely affect vision. The study is published in the November 24, 2004 online version of the journal Human Molecular Genetics.

Retinitis pigmentosa (RP) is one of the most common causes of blindness. It affects one in 3,500 people or approximately two million people worldwide. Patients with RP typically are diagnosed with night blindness and, as the disease progresses, they eventually lose all of their peripheral vision and a significant portion of their central vision.

Photoreceptor cells (known as rods and cones) are located in the eye’s retina and are responsible for converting light into electrical impulses for transmitting messages to the brain, according to Kang Zhang, M.D., Ph.D., the study’s senior author. This process of converting light to electrical signals in the retina requires a tremendous amount of energy which, in turn, creates waste in the form of carbon dioxide and bicarbonate.

According to the paper, patients in the study each had a mutation in which a defect in the process responsible for handling carbon dioxide waste and maintaining acid and base balance led to photoreceptor degeneration.

Zhang says the mutation inhibits function of a protein complex made up of carbonic anhydrase 4 (CA4) and Na+/Bicarbonate Co-transporter1 (NBC1) from doing its job of controlling acid and base balance. “In healthy eyes this acid waste is released from the retina and into the bloodstream via tiny blood vessels called the choriocapillaris which are located adjacent to the photoreceptors. When this doesn’t happen, we see the death of photoreceptor cells and the start of retinitis pigmentosa,” said Zhang.

The study also suggests additional research is needed to determine whether carbonic anhydrase inhibitors may affect vision. According to the study, “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.”

Zhang says it’s not clear how many cases of RP can be attributed to this newly discovered CA4 gene mutation. “However, we have already gained invaluable lessons from studying four families with this mutation. The next step is to begin working on a pharmaceutical intervention to counteract the effect of the gene mutations,” he said.

Although one of the three gene mutations in this study was independently reported by a group of researchers at the University of Cape Town and St. Louis University, Zhang says these new results indicate a completely different mechanism causing blindness.

In addition to Zhang, other investigators contributing to the new findings are from the University of Alberta, University College of London, Universitätsaugenklinik Tübingen, and University Medical Centre Nijmegen. Zhang is an assistant professor of ophthalmology and visual sciences at the Moran Eye Center. He is also an investigator for the Program in Human Molecular Biology and Genetics at the University of Utah’s Eccles Institute of Human Genetics.