In patients with retinitis pigmentosa (RP), crucial cells in the retina known as rods and cones die over time; night blindness eventually sets in; tunnel vision follows; and some individuals become totally blind over time. Although genetic causes have been found for many cases, around 40% of patients do not know the exact cause of their disorder, which can impede the development of effective treatments. Now, scientists have identified a novel genetic cause of RP. This report, which was published in Nature Genetics, may help scientists develop novel therapeutics or preventatives for this disorder,
This study began with a family in which members were affected by RP. The investigators had not found the genetic cause of their RP after analyzing known RP genes. The investigators eventually found that affected individuals in this family carried a causal variant in a gene known as RNU4-2.
Many genes have been well-characterized because they generate important proteins. But as genetic tools have become more advanced, scientists have found that there are also critical genes that are expressed, but do not lead to the production of any protein. Many of these genes, which are transcribed as RNA when they are active, lead to the production of something known as non-coding RNA. These non-coding RNAs are often involved in regulating the expression of other genes. RNU4-2 is a non-coding RNA that aids in the splicing of other gene transcripts.
This work has identified changes in the sequence of RNU4-2 that can lead to RP.
Other studies have previously linked RNU4-2 to some developmental disorders. But in this study, the researchers found a variation or genetic mutation that can alter a regulatory process that seems to be crucial for the health of the retina.
Additional work revealed four genes that can change, and lead to effects that are like what is seen from the RNU4-2 mutation.
After finding these mutations, the researchers analyzed the genetics of other individuals with RP who have not gotten a genetic diagnosis. This new mutation was found to account for about 1.4% of all RP cases in the world, or 153 individuals from 67 families, whose cases had not yet been genetically explained before this.
"This is a huge step forward," said study co-author Kim Rodenburg, a genetic researcher at Radboud University Medical Center (Radboudumc).
"This breakthrough goes beyond these specific genetic variants causing RP. It shows that we should also look beyond protein-coding genes,” noted corresponding study author Susanne Roosing, a molecular geneticist at Radboudumc.
"We've learned that changes in these RNA genes can be just as impactful as changes in protein-coding genes. This is fundamental knowledge that broadens our understanding of hereditary diseases,” added Rodenburg.
Sources: Radboud University, Nature Genetics
