Retinitis pigmentosa (RP) is a progressive condition of the retina that reduces the vision of affected individuals. Over time, photosensitive rod and cone cells in the retina gradually die, causing visual symptoms beginning with night blindness, and progressing to tunnel vision and, for some, complete blindness.
While there are over a hundred known genetic causes of RP, up to half of the affected patients have an unknown genetic foundation for their condition.
In one family, nine individuals—the father and eight children—were impacted by RP along with other genetic conditions.
“They came to us asking: what’s behind this? Is there one cause explaining all these conditions, or are multiple genes involved?” said Susanne Roosing, PhD, a molecular geneticist at Radboud University Medical Center (RadboudUMC). She is the lead researcher on a paper exploring the genetic cause of RP in this family and many others.
The team published their results in a paper titled, “De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa” in Nature Genetics.
“We did not find a cause in a known RP gene. So, we analyzed the entire DNA of the parents and children. That explained the other conditions, but not the RP. We knew then we had to look for a new cause. A huge challenge, but eventually we found a variation in the gene RNU4-2.”
RNU4-2 is a gene that produces a functional RNA that does not get transcribed into protein. RNU4, U4 small nuclear RNA (snRNA), binds with other snRNAs and proteins to form a complex involved with splicosomes. Mutations in RNU genes were previously identified as connected to neurodevelopmental disorders.
Researchers from RadboudUMC, along with global collaborators including researchers from the University of Basel, conducted a large-scale DNA analysis of 5,000 RP patients with an unknown genetic cause. Their analysis found both inherited and de novo mutations not only in RNU4-2, but also in four out of five paralogues of RNU6. These variants were identified in 135 patients spread over 67 families involved in the study.
“This is a huge step forward,” said Kim Rodenburg, a genetic researcher and doctoral candidate at RadboudUMC. “We’ve not only identified a new cause of blindness, but we also show that DNA segments that don’t make proteins are still crucial. Noncoding genes have never been linked to inherited retinal diseases.”
“They now know the source of their blindness,” Roosing added. “And they can make informed choices, such as using preimplantation genetic testing to prevent passing the condition to their children. That’s incredibly valuable.”
This work not only identified the genetic cause of RP in over 67 families but also further highlights the role that noncoding genes can have in genetic disorders. It also begs the question of what other diseases with unknown genetic origins are also due to variants or mutations in noncoding genes.
“We’ve learned that changes in these RNA genes can be just as impactful as changes in protein-coding genes,” commented Rodenburg. “This is fundamental knowledge that broadens our understanding of hereditary diseases.”
