Hundreds of genes linked to blindness could lead to new therapies

Hereditary eye diseases account for at least 2 million cases of blindness worldwide. A few hundred genes responsible for eye diseases have been identified, but in many cases the cause is unknown because not all ocular disease genes have been identified.

As a result, genetic testing can only determine the mutation responsible for blindness in 50-75% of blind children and young adults.

As an eye specialist and researcher, I am frustrated by the lack of treatment for my patients with genetic forms of blindness, such as retinitis pigmentosa, Stargardt's disease, and age-related macular degeneration. To solve this problem, my lab has started a study on the genes necessary for the normal formation and functioning of the eye. We discovered 347 genes that, if mutated, cause blindness in laboratory mice. Of these, 261 had never been badociated with vision loss before our study, which we recently published in the journal Communications Biology.

Knockout mice help identify more genes for blindness

Researchers first identified genes for eye disease in the late 1980s by studying in the United States families with inherited forms of retinitis pigmentosa, a retinal cell disease called rod photoreceptors in children and young adults, leading to blindness. Since then, more and more families have been studied to add to the list of blinding mutations in people.

To determine which genes are causing blindness, we took advantage of what is called knockout technology. The researchers design a knockout mouse by removing both copies of a single gene. This effectively removes it from the mouse genome. Anomalies result and provide clues to the function of the knocked-out gene. The genome of the mouse is similar to that of humans and contains about 22,000 to 25,000 genes. Until now, scientists around the world have neutralized approximately 7,000 genes in mice and the process of studying these mice is underway.

The invention of knockout mouse technology in the 1990s led to the identification of eye disease genes by studying the eyes of mice with targeted deletions. The International Mouse Phenotyping Consortium (IMPC), which brings together more than a dozen mouse biology centers in North America, Europe and Asia, aims to create a knockout mouse for each genome gene. of the mouse. The IMPC has created and carefully examined more than 4,364 knockout mice.

By badyzing the data recorded during eye examinations in all IMPC centers around the world, my colleagues and I found that 347 of these knockout mice, each representing a single deleted gene, had eye abnormalities determined by qualified ophthalmology experts. The anomalies sometimes involved the anterior structures of the eye, such as the eyelids, cornea and lens, and sometimes posterior structures, such as the retina and the optic nerve.

Testing the genes of eye disease in mice in humans

Since the genomes of mice and humans are similar, it is highly likely that these newly identified genes, if they are mutated, also cause eye diseases in humans. The next step is to study these newly implicated mouse genes in blind human patients. Specifically, we will badyze the genomes of patients whose previous genetic tests were unable to relate their condition to one of the previously known eye disease genes.

The addition of hundreds of new eye disease genes in this IMPC study will help ophthalmologists like me around the world to provide more accurate genetic diagnoses to our patients. To validate these genes in humans, we plan to create a panel of these 261 new genes that can be badyzed for mutations.

In addition, knockout mice will serve as publicly available research models for newly discovered eye disease genes. All of these knockout mice are available to all researchers and can be ordered from the IMPC repository for additional scientific studies and therapeutic discoveries. These mouse models can be used to test new drugs, gene therapies and stem cell approaches.

Knockout mice teach us about genetics

The scientific discoveries of the ICPM rapidly advance our understanding of the thousands of genes and molecules that underlie many human disease processes. In every organic system of the body, researchers discover many genes that have never been linked to a disease. The results of the IMPC project, including the genes for eye disease, could advance diagnostic capacity and identify new targets for new treatments.

I hope that ophthalmologists from leading universities and ophthalmic centers will cross our list of 261 new mouse eye disease genes with the genetic sequence of their human patients in which they found no mutations causing the disease.

We hope that our list of genes will guide our colleagues towards the genetic manager in many cases and will provide both a specific diagnosis and a way forward for the eventual treatment of families with inherited forms of blindness.

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