Radboudumc uncovers an unknown cause of blindness

Researchers at Radboudumc have discovered a new genetic cause of hereditary blindness. Their study shows that mutations in a specific segment of DNA, which plays a role in processing genetic information, can lead to retinitis pigmentosa. This eye disease affects about 1 in 5,000 people worldwide, causes “tunnel vision,” and can sometimes result in complete blindness. The discovery provides clarity for dozens of families around the world and opens up new possibilities for diagnosis and counseling in hereditary disorders.

Retinitis pigmentosa (RP) is an eye condition in which people first develop night blindness and later tunnel vision. This happens because the rod cells in the retina, which enable vision in low light, gradually die off. People often lose their entire vision as the cone cells, which are responsible for color vision, gradually deteriorate. Although more than 100 genes are known to cause RP, the genetic cause remains unresolved in 30-50% of patients, even after extensive DNA testing. Researchers at Radboudumc have now solved part of this puzzle.

From one to dozens of families

The discovery began with an American family with eight children in which blindness and other conditions occurred. “They came to us asking: what is behind this? Is there a single cause that explains all these conditions, or are different genes involved?” says lead researcher Susanne Roosing, a molecular geneticist at Radboudumc. “We found no cause in any of the known RP genes. We then analyzed the entire DNA of the parents and children. That allowed us to explain the other conditions. At that point, we knew we had to look for a new cause of RP. An enormously intensive task, but eventually we found a variant in the gene RNU4-2.”

The change that was found is located in a special gene, RNU4-2, which does not produce a protein but only RNA. RNA from this type of gene forms part of a support system that helps process genetic information, a step required before a cell can make proteins. Other changes in RNU4-2 have recently been shown to cause a developmental disorder. The variant found in the American family with RP, however, is located precisely at a hinge point in the RNA. As a result, an important regulatory mechanism in the retina no longer functions properly, which can ultimately lead to blindness.

Analysis of 5,000 patients

Following the initial discovery, the team, together with researchers from Basel and colleagues worldwide, conducted a large-scale analysis of the DNA of 5,000 patients whose RP etiology remained unknown. In addition to changes in RNU4-2, the researchers identified four similar genes, providing clarity for 153 people from 67 families about their hereditary condition. These variants now explain about 1.4 percent of all previously unexplained RP cases worldwide. “This is a huge step forward,” says Kim Rodenburg, a genetic researcher at Radboudumc. “We have not only found a new cause of blindness, but also shown that pieces of DNA that do not produce proteins can still be extremely important. Non-coding genes had never before been linked to inherited retinal diseases.”

Members of the American family that initiated the search are extremely pleased with this breakthrough. They did not expect that research into their genes would also help 66 other families. “They now know where the blindness comes from,” says Roosing. “And they can make informed choices—for example, using embryo selection and IVF to prevent passing the condition on to their children. That is of great value.”

A new chapter in genetics

This breakthrough extends beyond these specific genetic variants that lead to RP. It also demonstrates that not only protein-coding genes matter, but also the system’s “regulators.” The discovery offers researchers worldwide new opportunities to uncover the origins of hereditary disorders—and not just eye diseases. As Rodenburg explains: “We have learned that changes in these RNA genes can be just as impactful as changes in genes that do produce proteins. This is fundamental knowledge that broadens our understanding of hereditary disease.”