A study published in Nature Genetics reports that inherited and new (de novo) variants in genes encoding U4 and U6 small nuclear RNAs can cause autosomal dominant retinitis pigmentosa (RP), a hereditary condition that leads to progressive vision loss. RP is genetically complex, and many patients remain without a clear genetic diagnosis after standard testing.
Retinitis pigmentosa affects about two million people worldwide. Despite the use of exome and genome sequencing, up to half of cases do not receive a molecular diagnosis. In this study, researchers examined large international groups of patients with nonsyndromic RP and identified recurrent genetic variants in RNU4-2, which produces U4 RNA, and in four related RNU6 genes that produce U6 RNA. These variants were found in 153 affected individuals from 67 families.
U4 and U6 RNAs play a central role in the spliceosome, a cellular complex that processes messenger RNA before it is translated into protein. The disease-associated variants were all located in the same region of the U4/U6 structure, known as the three-way junction. This region interacts with spliceosomal proteins that are already known to cause autosomal dominant RP when altered. Laboratory studies showed that the RNA variants interfered with normal spliceosome assembly rather than causing widespread errors in RNA splicing.
Patients with RNU4-2 or RNU6 variants showed typical features of autosomal dominant RP, including night blindness and gradual loss of peripheral vision. The study also found that some individuals carrying these variants had few or no symptoms, a pattern known as “incomplete penetrance”. This variability is important for interpreting genetic test results and counseling affected families.
From a diagnostic perspective, the authors estimate that variants in RNU4-2 and RNU6 genes may explain about 1.4 percent of RP cases that previously lacked a genetic diagnosis. These genes are often missed in routine testing because they encode noncoding RNAs, which may not be included in standard sequencing panels or prioritized during analysis.
Overall, the study shows that noncoding RNA genes can play an important role in inherited disease. Including spliceosomal RNA genes in genetic testing may help identify the cause of RP in some patients who remain undiagnosed after conventional analysis.
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