Variants in the RNU4-2 gene are a previously unrecognized cause of an autosomal dominant form of the inherited eye disease retinitis pigmentosa (RP). According to a study published in Nature Genetics, researchers identified heterozygous, disease-causing variants in RNU4‑2 and in four additional snRNA genes (RNU6‑1, RNU6‑2, RNU6‑8, RNU6‑9) in individuals with non-syndromic RP. Until now, RNU4‑2 variants had mainly been associated with a neurodevelopmental disorder known as ReNU syndrome.

RNU4‑2 does not encode a protein but gives rise to a small nuclear RNA (snRNA) called U4. Together with specific proteins, the snRNAs U1, U2, U4, U5 and U6 assemble into small nuclear ribonucleoproteins (snRNPs), which form the building blocks of the spliceosome. This large RNA–protein complex is responsible for removing non-coding segments (introns) from precursor mRNA and joining the coding segments (exons), a key step on the way from gene to functional protein. U4, produced from RNU4‑2, pairs with U6 to form an RNA duplex that, together with U5, constitutes the so‑called tri‑snRNP within the spliceosome. In the study, the investigators detected both inherited and de novo variants in RNU4‑2 and in four RNU6 paralogues in 153 affected individuals from 67 families, all located in a specific region of the U4/U6 RNA duplex that interacts directly or indirectly with RP‑associated splicing factors (PRPF31, PRPF3, PRPF6, PRPF8). These variants do not appear to abolish splicing globally, but rather interfere with the maturation and assembly of snRNP particles.

Retinitis pigmentosa is characterized by progressive degeneration of the retina, which can ultimately lead to blindness. The condition affects roughly 1 in 4,000 people worldwide and can result from pathogenic changes in many different genes. Based on their data, the authors estimate that disease-causing variants in RNU4‑2 and the RNU6 paralogues may account for around 3% of genetically unsolved cases of autosomal dominant RP.