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Nov. 23, 2004 -- 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
(http://hmg.oupjournals.org).
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.
Funding for the study was provided by the National Institutes of
Health, The Foundation Fighting Blindness, The Ruth and Milton Steinbach
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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