Geneticists Discover Link to Inherited Retinal Disease

Researchers at The University of Texas School of Public Health at Houston have discovered a surprising link between a well-studied gene involved in DNA synthesis and inherited retinal diseases.

A research study published in the March issue of Human Molecular Genetics reports mutations in inosine monophosphate dehydrogenase 1, or IMPDH1, are expected to cause from 5 to 10 percent of one form of retinitis pigmentosa, a degenerative eye disease that affects approximately one out of 3,500 people worldwide.

"Both forms of IMPDH have been extensively studied for 20 years, but no one had thought to look at its function in the eye," said Dr. Sara Bowne, lead author of the study and research associate in the Human Genetics Center at the UT-Houston School of Public Health. "Several classes of drugs are known to affect IMPDH proteins, and this suggests that treatments may someday be available for people with this form of retinitis pigmentosa."

The retina is a complex neurological tissue that detects and absorbs light, transmitting it to the brain where it is processed as visual images. Due to slow retinal degeneration, individuals with retinitis pigmentosa experience night blindness, gradual loss of peripheral vision, and eventual blindness later in life.

The body produces two forms of this same molecule, IMPDH1 and IMPDH2, and both play critical roles in nucleotide (precursors for DNA and RNA) synthesis. Interestingly, IMPDH1 alone seems to be critical for normal vision, and mutations in this gene result in the RP10 form of autosomal dominant RP (adRP). (When a genetic disease is autosomal dominant, only one copy of the mutated gene is required to cause disease and the gene in question is not found on chromosome X or Y, the chromosomes that determine sexuality.)

Dr. Stephen Daiger is the director of the Laboratory for Inherited and Molecular Diagnosis of Inherited Eye Diseases at UT-Houston, where Drs. Bowne and Lori S. Sullivan, associate professor in the Human Genetics Center, work together to unravel the unexpected role of IMPDH1 in human vision.

"It is interesting from a scientific point of view," said Dr. Daiger, who is also professor of human genetics at the UT-Houston School of Public Health and a faculty member at the UT-Houston Graduate School of Biomedical Sciences. "This enzyme is found throughout the body, yet we find that individuals with mutations in the IMPDH1 gene have no other physical problems except retinal degeneration."

Research from the University of North Carolina at Chapel Hill shows that when the mouse IMPDH1 gene is removed, the mice appear to be normal. However, Dr. Bowne said, no one thought to find out if the mice could actually see. As it turns out, it is difficult to tell if a laboratory mouse is blind unless they are tested in specialized behavioral or physiological studies.

"Our collaborators at UNC may have never known about the effects in the retina if IMPDH1 hadn’t been found to be associated with adRP," Dr. Bowne said.

Mutations in IMPDH1 have been identified in six adRP families to date, but Dr. Bowne said that number is expected to increase as other families with histories of RP are tested.

"We are setting up collaborations with IMPDH researchers around the world," Bowne said. "Because we all share the same goal of curing this disease, we can work together and combine our areas of expertise."

Discovery of IMPDH1’s role in inherited eye diseases, combined with all that is currently known about the family of IMPDH proteins, should increase the urgency for the development of IMPDH1-specific drugs.

"We’re not starting from ground zero, and our finding may one day lead to faster development of treatments or cures for this debilitating disease," Dr. Bowne said.

Research in Dr. Daiger’s laboratory is supported by grants from the Foundation Fighting Blindness, the George Gund Foundation, the Schissler Foundation, the William Stamps Farish Fund, the M.D. Anderson Foundation, the John S. Dunn Foundation, the Alfred W. Lasher III Fund, and the Hermann Eye Fund. Dr. Bowne has individual funding from the President’s Research Scholarship from UT-Houston and the National Eye Institute of the National Institutes of Health.

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©2006 Texas Medical Center

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