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Home » News and Events » Defective Mouse Gene Linked to Childhood Blindness, November 30, 1998
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NATIONAL INSTITUTES OF HEALTH
National Eye Institute

November 30, 1998

Defective Mouse Gene Linked to Childhood Blindness

For centuries, children have been reciting the Mother Goose nursery rhyme, "Three Blind Mice." Now, researchers studying a new strain of blind mice may know what caused their blindness and, more importantly, how this knowledge might someday prevent some forms of blindness in humans.

Scientists at the National Eye Institute, part of the Federal government's National Institutes of Health, have discovered how a defective gene in mice leads to blindness. Correcting this deficiency may, in the future, restore vision to people who are born with blinding conditions called retinal dystrophies. In these disorders, there is a breakdown in the process that allows us to see. A paper detailing these findings is published in the December 1998 issue of Nature Genetics.

"This research provides hope for some people with severe retinal dystrophy, such as Leber's congenital amaurosis, who are born blind or lose their vision in early childhood," said Dr. Carl Kupfer, director of the National Eye Institute. "These results may allow scientists someday to develop treatments that will restore vision to people who have been blind for most of their lives."

Researchers previously knew that the gene RPE65 produces a protein, also called RPE65, that is essential for normal vision. This RPE65 protein is confined to the retinal pigment epithelium cells, that process vitamin A in the visual system. But why is this protein essential? What contributions does this protein make to the visual system?

To answer these questions, scientists "disrupted" the RPE65 gene in mice, that is 95 percent similar to the RPE65 gene in humans. The researchers found that the RPE65-deficient mouse was not producing a form of vitamin A called 11-cis-retinal that is essential for vision. This, in turn, led to a breakdown in the visual cycle, causing severe blindness.

"This research gives scientists a fundamental understanding about the underlying causes of severe retinal dystrophy," said Dr. Michael Redmond of the National Eye Institute's Laboratory of Retinal Cell and Molecular Biology and the principal investigator of the study. "Scientists first need to understand the cause of vision loss before they can develop treatments. If we can reverse the blindness in mice, we can think about reversing the blindness in humans."

In the RPE65-deficient mice, Dr. Redmond found that the eye's rod photoreceptors—which allow us to see in dim light—were not working. But why not? Upon further investigation, Dr. Redmond and colleagues discovered that the rod photoreceptors were not producing a crucial ingredient called rhodopsin, which rod photoreceptors need to convert light into signals that are sent to the brain. It is these neuronal signals that allow us to see. Dr. Redmond and colleagues discovered that the reason rhodopsin was not being produced was because one of its main components, 11-cis-retinal, was not being generated. They concluded that severe blindness resulted in the mice because the RPE65-deficient retina did not produce the 11-cis-retinal vitamin A, which was essential to produce rhodopsin.

The researchers also discovered that unlike the rod photoreceptors, the eye's cone photoreceptors—which allow us to see in bright light—were not affected by the lack of the RPE65 gene. "This tells us that the cone photoreceptors in mice must have their own supply of 11-cis retinal vitamin A," Dr. Redmond said. "But where is it coming from? Both the rods and cones need 11-cis retinal vitamin A to work correctly."

The research revealed another important discovery: Vitamin A accumulates in the RPE65-deficient retinal pigment epithelium cells. In the normal visual cycle, the retinal pigment epithelium cells convert the dietary form of vitamin A into the visual 11-cis retinal form. "When you eat a carrot, vitamin A (which is converted from the carrot's beta-carotene) goes to the retinal pigment epithelium cells, which convert the vitamin into 11-cis retinal," he said. "The 11-cis retinal is then combined with another protein (opsin) to make rhodopsin. But the defective retinal pigment epithelium cells do not convert the vitamin A into 11-cis retinal—the vitamin just accumulates in these cells. Scientists have been searching for the enzyme that converts the dietary form of vitamin A to the 11-cis form. This is a major challenge, but these mice tell us that RPE65 is a major player in this conversion process.

"When you take away the RPE65 protein from the retinal pigment epithelium cells in animals, the conversion process of vitamin A stops dead in its tracks," Dr. Redmond said. "By reasoning, this indicates that the RPE65 protein is central to that conversion."

Dr. Redmond said that these findings "provide a possible avenue for treating people with severe vision loss caused by defects in the RPE65 gene. Despite the deficient RPE65 gene, the photoreceptors appear to survive. Perhaps if we replace the defective RPE65 gene with a normal gene, we can use the framework already in the eye and restore visual sensitivity. It won't be easy, but we have a starting point."

The National Eye Institute, part of the National Institutes of Health, is the Federal government's lead agency for vision research and supports between 70-80 percent of basic and applied vision research in the United States.

Why RPE65 is Important to Vision
Visual Process with Normal RPE65
vs.
Visual Process with Defective RPE65
  • You eat a carrot.
  • You eat a carrot.

  • The body converts the carrot's beta-carotene into vitamin A and sends some of the vitamin A to the eye's retinal pigment epithelium cells.

  • The body converts the carrot's beta-carotene into vitamin A and sends some of the vitamin A to the eye's retinal pigment epithelium cells.

  • The retinal pigment epithelium cells convert the vitamin A into the visual 11-cis retinal form of the vitamin.

  • The retinal pigment epithelium cells are unable to convert the vitamin A into the visual 11-cis retinal form of the vitamin. Instead, vitamin A accumulates in these cells.

  • This 11-cis retinal form of vitamin A is delivered to the rod photoreceptors.

  • Because the 11-cis retinal form of vitamin A is not generated, it is not delivered to the rod photoreceptors.

  • The rod photoreceptors combine the 11-cis retinal with a protein called opsin to make a protein called rhodopsin.

  • Without the 11-cis retinal form of vitamin A, the rod photoreceptors cannot make the protein rhodopsin.

  • When your eyes view an object, light reflected from that object is focused on the eye's rod photoreceptors, which uses rhodopsin to convert the light into signals that are sent to the brain. This allows us to see.

  • When your eyes view an object, light reflected from that object is focused on the eye's rod photoreceptors. However, because the rod photoreceptors cannot make the protein rhodopsin, the light cannot be converted into signals that are sent to the brain. This prevents us from seeing the image.

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June 2001

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