| 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, S.E.; Iglesias-Romero, A.B.; Boonen, E.G.M.; Ullah, M.; Zomer, N.; Folcher, M.; Bijon, J.; Holtes, L.K.; Tsang, S.H.; Corradi, Z.; Freund, K.B.; Shliaga, S.; Panneman, D.M.; Hitti-Malin, R.J.; Ali, M.; AlTalbishi, A.; Andréasson, S.; Ansari, G.; Arno, G.; Astuti, G.D.N.; Ayuso, C.; Ayyagari, R.; Banfi, S.; Banin, E.; Barakat, T.S.; Barboni, M.T.S.; Bauwens, M.; Ben-Yosef, T.; Bernard, V.; Birch, D.G.; Biswas, P.; Blanco-Kelly, F.; Bocquet, B.; Boon, C.J.F.; Branham, K.; Bremond-Gignac, D.; Britten-Jones, A.C.; Bujakowska, K.M.; Burin des Roziers, C.; Cadena, E.L.; Calzetti, G.; Cancellieri, F.; Cattaneo, L.; Chadderton, N.; Charbel Issa, P.; Coutinho-Santos, L.; Daiger, S.P.; De Baere, E.; De Bruyne, M.; de la Cerda, B.; De Roach, J.N.; De Zaeytijd, J.; Derks, R.; Dhaenens, C.-M.; Dudakova, L.; Duncan, J.L.; Farrar, G.J.; Feltgen, N.; Fenner, B.J.; Fernández-Caballero, L.; Ferraz Sallum, J.M.; Gana, S.; Garanto, A.; Gardner, J.C.; Gilissen, C.; Gonzàlez-Duarte, R.; Goto, K.; Griffiths-Jones, S.; Haack, T.B.; Haer-Wigman, L.; Hardcastle, A.J.; Hayashi, T.; Héon, E.; Hoefsloot, L.H.; Hoischen, A.; Holtan, J.P.; Hoyng, C.B.; Ibanez, M.B.B.; Inglehearn, C.F.; Iwata, T.; Jensson, B.O.; Jones, K.; Kalatzis, V.; Kamakari, S.; Karali, M.; Kellner, U.; Klaver, C.C.W.; Knézy, K.; Koenekoop, R.K.; Kohl, S.; Kominami, T.; Kühlewein, L.; Lamey, T.M.; Leibu, R.; Leroy, B.P.; Liskova, P.; Lopez, I.; López-Rodríguez, V.R.D.J.; Mahieu, Q.; Mahroo, O.A.; Manes, G.; Mansard, L.; Martín-Gutiérrez, M.P.; Martins, N.; Mauring, L.; McKibbin, M.; McLaren, T.L.; Meunier, I.; Michaelides, M.; Millán, J.M.; Mizobuchi, K.; Mukherjee, R.; Nagy, Z.Z.; Neveling, K.; Ołdak, M.; Oorsprong, M.; Pan, Y.; Papachristou, A.; Percesepe, A.; Pfau, M.; Pierce, E.A.; Place, E.; Ramesar, R.; Ramond, F.; Rasquin, F.A.; Rice, G.I.; Roberts, L.; Rodríguez-Hidalgo, M.; Ruiz-Ederra, J.; Sabir, A.H.; Sajiki, A.F.; Sánchez-Barbero, A.I.; Sarma, A.S.; Sangermano, R.; Santos, C.M.; Scarpato, M.; Scholl, H.P.N.; Sharon, D.; Signorini, S.G.; Simonelli, F.; Sousa, A.B.; Stefaniotou, M.; Stefansson, K.; Stingl, K.; Suga, A.; Sulem, P.; Sullivan, L.S.; Szabó, V.; Szaflik, J.P.; Taurina, G.; Thiadens, A.A.H.J.; Toomes, C.; Tran, V.H.; Tsilimbaris, M.K.; Tsoka, P.; Vaclavik, V.; Vajter, M.; Valeina, S.; Valente, E.M.; Valentine, C.; Valero, R.; Valleix, S.; van Aerschot, J.; van den Born, L.I.; Van Heetvelde, M.; Verhoeven, V.J.M.; Vincent, A.L.; Webster, A.R.; Whelan, L.; Wissinger, B.; Yioti, G.G.; Yoshitake, K.; Zenteno, J.C.; Zeuli, R.; Zuleger, T.; Landau, C.; Jacob, A.I.; Lin, S.; Cremers, F.P.M.; Lee, W.; Ellingford, J.M.; Stanek, D.; Roosing, S.; Rivolta, C. |
| Publisher Information: |
Nature Research |
| Publication Year: |
2026 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| 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 |
| File Description: |
text |
| Language: |
English |
| ISSN: |
1061-4036 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/238863/3/s41588-025-02451-4.pdf; Quinodoz, M., Rodenburg, K., Cvackova, Z. et al. (185 more authors) (2026) De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nature Genetics, 58. pp. 169-179. ISSN: 1061-4036 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/238863/ |
| Rights: |
cc_by_nc_nd_4 |
| Accession Number: |
edsbas.E1A215F9 |
| Database: |
BASE |