RPE65 : A Blinding Gene

The participants in the Children’s Hospital eye trials have a particular form of Leber’s congenital amaurosis: they carry mutations in a gene called RPE65 that eventually lead to near or total blindness. Here’s how the condition takes root.

Healthy human vision depends on a cascade of complicated chemical and electrical messages. First, light strikes photoreceptor cells in the retina. This triggers a chemical reaction that turns the light into electrical impulses, which travel through the optic nerve to the brain’s visual cortex for interpretation.

That intermediate step in the retina depends on the transformation of a protein called rhodopsin, which includes a molecule called 11-cis-retinal. The gene mutated in LCA patients makes an enzyme that produces 11-cis-retinal. In other words, without a healthy version of RPE65, rhodopsin can’t do its job properly.

To make matters worse, RPE65 mutations disrupt the biochemical cascades in a way that results in toxic molecules. These accumulate over time and slowly kill photoreceptor cells. This explains why LCA patients’ vision gets worse over time.

This is also why High was so interested in doing gene therapy on children with the disease. And the team’s data support that logic. “After the therapy, we found that the measure of the visual response tracks pretty closely with age,” she says. “The younger the subject, the better the response.”

-- Virginia Hughes
HHMI Bulletin, August 2011

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