The findings could improve diagnostic rates and influence future therapeutic strategies.

Retinitis pigmentosa is a genetic disorder that leads to progressive vision loss, typically beginning with night blindness and narrowing of the visual field. It affects an estimated 2 million people worldwide. Despite advances in DNA sequencing, a definitive genetic cause remains unidentified in a substantial proportion of patients, limiting accurate prognosis, genetic counseling and eligibility for clinical trials.

The study, published in Nature Genetics, focused on genes that do not encode proteins but instead produce small RNA molecules that form part of the spliceosome — a cellular complex responsible for RNA splicing. RNA splicing is the process by which cells assemble genetic messages by removing nonessential segments and joining the correct fragments together before producing proteins.

While genes are often described as recipes for proteins, cells must first process the genetic instructions through RNA splicing. This process is carried out by the spliceosome, which consists of both proteins and short RNA molecules that help position precise cutting and joining sites.

Researchers investigated whether mutations in genes encoding these small RNA components could underlie unexplained cases of retinitis pigmentosa. Previous studies had linked variants in the RNU4-2 gene to neurodevelopmental disorders. The team examined whether specific variants in RNU4-2 and related U6 RNA genes might instead be associated with retinal degeneration.

The researchers identified recurring DNA changes consistent with dominant inheritance, in which a mutation in a single copy of a gene is sufficient to cause disease. The variants affected the RNU4-2 gene and four closely related U6 RNA genes: RNU6-1, RNU6-2, RNU6-8 and RNU6-9.

In total, the variants were detected in 153 individuals from 67 families with nonsyndromic retinitis pigmentosa, meaning the condition was confined to the eyes without other systemic symptoms. Some variants were inherited, while others arose as de novo mutations in affected individuals whose parents did not have the disease.

The mutations clustered in a specific region of the RNA molecules where U4 and U6 RNAs interact to form a key component of the splicing machinery. This region is known to interact with proteins such as PRPF31 and PRPF3, which have previously been implicated in dominant forms of retinitis pigmentosa. The findings suggest that the disease process affects the same cellular pathway, but originates in RNA rather than protein-coding genes.

Based on analyses of thousands of cases, the researchers estimate that harmful variants in RNU4-2 and U6 RNA genes may account for approximately 1.4% of previously unsolved cases of retinitis pigmentosa.

When the team examined patients’ blood cells for evidence of major splicing errors, they did not observe significant abnormalities. The detected differences were rare and subtle. Additional experiments suggested that the mutations may cause a slight slowdown at an early stage of spliceosome assembly, particularly during the interaction between U4 and U6 components. Such subtle defects may disproportionately affect the retina, a tissue with high demand for efficient RNA splicing.

The findings also have implications for genetic testing. Standard diagnostic panels typically focus on protein-coding genes and may overlook small RNA genes or assign them lower priority. Including these regions in routine testing could increase the number of patients who receive a definitive molecular diagnosis, clarifying inheritance patterns and risks for family members.

The results may also influence therapeutic development. In dominant genetic diseases, adding a normal copy of a gene may not be sufficient if a single altered copy can cause disease. In such cases, strategies aimed at silencing or repairing the defective version — potentially through RNA-targeted approaches — may be more appropriate. (PAP)

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