Rare retinal diseases: detective work for the eyesight

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Night blindness is a typical symptom of the retinal disease retinitis pigmentosa
Night blindness is a typical symptom of the retinal disease retinitis pigmentosa in its early stages. (Image: A street in Basel, pixabay, edited)
A team at the Institute of Molecular and Clinical Ophthalmology Basel (IOB) and the University of Basel is hunting for the causes of hereditary retinal diseases. By doing so, the researchers are laying an important foundation for gene therapies aimed at combating vision loss.

There are over 20 rare genetic diseases that lead to progressive degradation of the retina and vision loss - and these diseases, which have names like retinitis pigmentosa or macular dystrophy, are extremely varied in terms of their genetics.

For example, the best known of the hereditary retinal diseases, retinitis pigmentosa, can be triggered by changes in any one of 65 genes. Conversely, the overwhelming majority of rare diseases are caused by changes to just one specific gene.

In cases of retinitis pigmentosa, patients initially notice that they can no longer see well at night. In a later stage of the disease, they lose their peripheral vision - their field of vision narrows to a tunnel that gets smaller and smaller before closing altogether. Macular dystrophy works the other way around: patients first lose the center of their field of vision, such that they can no longer recognize faces, read signs or see their mobile phone screen.


Hopes for tackling diseases of this kind rest on gene therapies aimed at maintaining or restoring vision. Thanks to methods such as the Crispr-Cas9 gene scissors, as well as refinements of this technology, it may be possible to correct the error in the affected gene. Using this technique, it would be easier to treat the eye than many other organs because it is more accessible for therapy. The only problem is that you first need to clarify which gene is in need of repair.

A needle in a haystack

So far, there are already over 300 known genes in which mutations can lead to vision loss. Thanks to modern DNA sequencing and computer-based analyses, researchers led by Professor Carlo Rivolta have described several new genes in recent years. "As well as DNA from patients examined at the University Hospital Basel (Augenspital), we also receive unexplained cases from other hospitals. In two out of three instances, we’re able to identify the genetic cause," explains the leader of the Ophthalmic Genetics research group at the Institute of Molecular and Clinical Ophthalmology Basel (IOB), which is associated with the University of Basel.

However, this is anything but a trivial task. Rivolta compares looking for the decisive genetic change to searching for a single grain of sand in two trash cans full of the material. Given that the genotype varies slightly from person to person at many thousands of locations, how is one supposed to identify the location that triggered the disease?

Filtering and comparing

It’s above all a filtering process, says Rivolta. "By comparing the patient’s genetic material with that of many other people, we can separate out frequently occurring variants in the DNA." Particularly rare variants are marked as suspicious and compared with the genome data of other people affected by retinal diseases.

In the human genome, most genes are present in two copiesone inherited from the father and one from the mother. Most retinal diseases are recessive - in other words, provided that only one copy of the gene carries a mutation, the person will be a "healthy carrier" (see box "Risk of consanguinity" below). Symptoms only appear if there are defects in both copies of the gene. These defects can be changes at different positions of the gene’s DNA sequence.

Silent mutations are not so silent after all

The proportion of unexplained cases continues to shrink thanks to elaborate genotype analyses such as those developed by Rivolta’s team, among others - particularly since there has been a rethink around what to search for: "For example, in the past, almost no attention was paid to silent mutations," Rivolta explains. These are changes in the DNA code that don’t actually cause any change in the sequence of amino acid building blocks within the protein. Researchers now know that even mutations of this kind can severely disrupt protein production. Something similar is true of mutations that lie outside the actual coding sequence of the genotype.

Rivolta is convinced that it will be possible to treat many retinal diseases using gene therapies in the not all too distant future. He says that there is certainly interest on the part of industry and that, if a new gene therapy is developed, there are relevant databases that could be used to recruit patients who stand to benefit from treatment - all thanks to the detective work of geneticists.


In the course of their analyses, the researchers working under Carlo Rivolta also investigated how many people in the population are healthy carriers of mutations that lead to retinal diseases if they affect both alleles. This work indicated that approximately every second person is a healthy carrier. However, because the mutations can occur in over 300 different genes, it’s very rare for two people carrying a mutation in exactly the same gene to have a child together.

One exception are couples who are blood relatives: given that the genetic mutation is passed on through the family tree, two healthy carriers who are distantly related to one another can pass the same mutation on to joint offspring. "Couples who are blood relatives have the highest risk of producing offspring with a rare retinal disease," says Rivolta. He adds that, on average, they are at even greater risk than unrelated parents who both suffer from a rare retinal disease. "In their case, it’s very likely that different genes are affected - and since the offspring only inherits one mutated copy of each gene, the child will most likely become a healthy carrier."

In a multi-part series of articles between International Neglected Disease Day (30 January) and Rare Disease Day (29 February), we highlight research at the University of Basel that aims to improve our understanding of such diseases and drive forward new therapeutic approaches.