New Look at Troublesome Gene Sheds Light on Eye Disease

Scientists in the Human Genetics Center of The University of Texas School of Public Health are on the hunt for the genes responsible for a form of retinitis pigmentosa, a hereditary eye disease that can lead to blindness. They knew that a gene named PRPF31 was bad news. But they didn’t know how bad.

New mutations related to retinitis pigmentosa were discovered in a known gene by, from left, Lori S. Sullivan, Ph.D.; Stephen P. Daiger, Ph.D.; and Sara J. Bowne, Ph.D., at the UT School of Public Health.

Photo by Rob Cahill

Initially blamed for one of every 20 cases of autosomal dominant retinitis pigmentosa (RP), the PRPF31 gene is actually responsible for one of every 12 cases, ranking it near the top of known genetic causes, according to a study in the laboratory of Stephen P. Daiger, Ph.D., the Thomas Stull Matney, Ph.D., Professor of Environmental and Genetic Sciences.

More than 100,000 Americans suffer from RP, and the dominant form accounts for 20 to 40 percent of the total. The disease can be passed from generation to generation and may affect dozens of members in a single family. It impairs photoreceptor cells in the retina that convert light into electrical impulses for transfer to the brain. Symptoms include night blindness and tunnel vision. There is no cure at present.

We’re Missing So Much

“We didn’t realize that we were missing so much,” said Lori S. Sullivan, Ph.D., a faculty associate in the Human Genetics Center and lead author of the study published in the October 2006 issue of Investigative Ophthalmology & Visual Science.

Fellow investigator, Sara J. Bowne, Ph.D., a Human Genetics Center research scientist, added that the study furthers their understanding of the underlying biology of autosomal dominant RP.

Researchers were missing disease-causing mutations caused by copy number variation, large changes in the human genome involving strings of thousands of DNA nucleotides (chemical compounds that make up DNA). The recent discovery of these insertions, deletions, duplications and complex multi-site variants in DNA is causing researchers to take a new look at genes.

First with New Technology

PRPF31 is the first autosomal dominant RP gene to be screened with the new copy number variation technology. Plans are under way to test the other autosomal dominant RP genes for copy number variation, said Daiger, who also is on the faculty at the UT Graduate School of Biomedical Sciences at Houston and an adjunct professor in the Department of Ophthalmology and Visual Science at the UT Medical School at Houston.

To date, scientists have found 185 genes causing inherited retinal diseases, said Daiger, lead author in another article published in the Feb. 12 issue of Archives of Ophthalmology. These are big accomplishments, Daiger said, when you consider that the first gene causing retinitis pigmentosa was discovered in 1990.

“A reasonable hope is that within five years, molecular testing of newly diagnosed patients with RP will be a routine part of clinical practice and will uncover the underlying disease-causing mutation (or mutations) in at least 90 percent of the cases,” he said. Knowing the underlying genetic cause will be essential for enrolling patients in clinical trials, a few of which have begun already or will begin shortly.

Treatment Options

“We look forward to the day when we can offer treatment options to autosomal dominant RP patients,” said Richard S. Ruiz, M.D., professor and chairman of the Department of Ophthalmology and Visual Science. Physicians currently assist these patients by counseling on the nature of the disease, offering guidance on career opportunities and providing information on genetic testing, Braille and mobility.

Ruiz, holder of the John S. Dunn Distinguished University Chair, said he expects “a rapid onset” of treatment trials involving gene therapy, medications and other treatments based on the work of Daiger and others.

These studies were supported by the William Stamps Farish Fund, the Gustavus and Louise Pfeiffer Research Foundation, Hermann Eye Fund, the National Institutes of Health and The Foundation Fighting Blindness.

Established in 1994, the Laboratory for Molecular Diagnosis of Inherited Eye Diseases is a joint project of the Hermann Eye Center, the Department of Ophthalmology and Visual Science in the Medical School, and the Human Genetics Center in the School of Public Health.

By Rob Cahill, Institutional Advancement

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