| Title: |
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa |
| Authors: |
Quinodoz, M; Rodenburg, K; Cvackova, Z; Kaminska, K; de Bruijn, SE; Iglesias-Romero, AB; Boonen, EGM; Ullah, M; Zomer, N; Folcher, M; Bijon, J; Holtes, LK; Tsang, SH; Corradi, Z; Freund, KB; Shliaga, S; Panneman, DM; Hitti-Malin, RJ; Ali, M; AlTalbishi, A; Andréasson, S; Ansari, G; Arno, G; Astuti, GDN; Charbel Issa, P |
| Publisher Information: |
Nature Research |
| Publication Year: |
2026 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s41588-025-02451-4 |
| Availability: |
https://doi.org/10.1038/s41588-025-02451-4; https://ora.ox.ac.uk/objects/uuid:2428ce6c-9be2-4dc6-99f4-53199eeff183 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) |
| Accession Number: |
edsbas.20E46BC1 |
| Database: |
BASE |