Blindness Fish

Zebrafish being fed / Novartis AG

A genetic variant which causes congenital blindness has been discovered in zebrafish, potentially opening new avenues for treatment for the condition in humans. The research, published in Science Reports today, was completed by researchers at the Okinawa Institute of Science and Technology (OIST) Graduate University.

Leber Congenital Amaurosis (LCA) is one of the most common causes of child blindness and is responsible for almost 5% of all visual impairments. While it’s known that the disease is recessive, heritable, and that it is caused by impairments in a gene involved in eye development, the underlying mechanism of the condition is unclear. LCA causes the rods and cones (photoreceptors that are responsible for capturing light and converting it into visual information) in a patient’s eyes to either become deformed or to be entirely absent, eliminating their ability to detect light.

Previous work has linked 24 separate genes to LCA in both humans and mice, including the aryl hydrocarbon receptor interacting protein like 1 (Aipl1) gene. When any one of these genes is damaged, it can inhibit normal ocular development or induce photoreceptor degeneration, causing LCA.

Zebrafish have retinas that are rich with cones and visual acuity can be measured very simply, meaning that they have become a very useful model for ocular investigations. The team behind this study therefore examined the genetics of a mutated zebrafish which did not react to any visual stimuli. They found that zebrafish have two copies of the Aipl1 gene, Aipl1a which is active in rods and Aipl1b which is active in cones, and their mutant zebrafish had a malfunctioning Aipl1b gene, resulting in deformed cones. Rods remained unaffected.

The team then revealed that Aipl1 played a critical role in stabilising cGMP-photodiesterase 6 and guanylate cyclase, two enzymes that mediate the process of converting light into neural signals (phototransduction). Without these functional enzymes, the photoreceptors are unable to send signals to the brain for processing and so the mutated zebrafish (known as gosh) cannot respond to visual stimuli.

It is possible that this work will help to direct future investigations into LCA in humans, particularly in relation to the Aipl1 gene.

“The gosh mutant is a good model for understanding the molecular and cellular mechanism of cone cell death and the pathological process of human LCA,” said Maria Iribarne, Ph.D., first author of the study. “Hopefully, this new knowledge will help to find a future cure for patients who suffer such a devastating disease as LCA.”