AUTHORS
Mathieu Quinodoz, Kim Rodenburg, Zuzana Cvackova, Karolina Kaminska, Suzanne E. de Bruijn, Ana Belén Iglesias-Romero, Erica G. M. Boonen, Mukhtar Ullah, Nick Zomer, Marc Folcher, Jacques Bijon, Lara K. Holtes, Stephen H. Tsang, Zelia Corradi, K. Bailey Freund, Stefanida Shliaga, Daan M. Panneman, Rebekkah J. Hitti-Malin, Manir Ali, Ala’a AlTalbishi, Sten Andréasson, Georg Ansari, Gavin Arno, Galuh D. N. Astuti, Carmen Ayuso, Radha Ayyagari, Sandro Banfi, Eyal Banin, Tahsin Stefan Barakat, Mirella T. S. Barboni, Miriam Bauwens, Tamar Ben-Yosef, Virginie Bernard, David G. Birch, Pooja Biswas, Fiona Blanco-Kelly, Beatrice Bocquet, Camiel J. F. Boon, Kari Branham, Dominique Bremond-Gignac, Alexis Ceecee Britten-Jones, Kinga M. Bujakowska, Cyril Burin des Roziers, Elizabeth L. Cadena, Giacomo Calzetti, Francesca Cancellieri, Luca Cattaneo, Naomi Chadderton, Peter Charbel Issa, Luísa Coutinho-Santos, Stephen P. Daiger, Elfride De Baere, Marieke De Bruyne, Berta de la Cerda, John N. De Roach, Julie De Zaeytijd, Ronny Derks, Claire-Marie Dhaenens, Lubica Dudakova, Jacque L. Duncan, G. Jane Farrar, Nicolas Feltgen, Beau J. Fenner, Lidia Fernández-Caballero, Juliana M. Ferraz Sallum, Simone Gana, Alejandro Garanto, Jessica C. Gardner, Christian Gilissen, Roser Gonzàlez-Duarte, Kensuke Goto, Sam Griffiths-Jones, Tobias B. Haack, Lonneke Haer-Wigman, Alison J. Hardcastle, Takaaki Hayashi, Elise Héon, Lies H. Hoefsloot, Alexander Hoischen, Josephine P. Holtan, Carel B. Hoyng, Manuel Benjamin B. Ibanez IV, Chris F. Inglehearn, Takeshi Iwata, Brynjar O. Jensson, Kaylie Jones, Vasiliki Kalatzis, Smaragda Kamakari, Marianthi Karali, Ulrich Kellner, Caroline C. W. Klaver, Krisztina Knézy, Robert K. Koenekoop, Susanne Kohl, Taro Kominami, Laura Kühlewein, Tina M. Lamey, Rina Leibu, Bart P. Leroy, Petra Liskova, Irma Lopez, Victor R. de J. López-Rodríguez, Quinten Mahieu, Omar A. Mahroo, Gaël Manes, Luke Mansard, M. Pilar Martín-Gutiérrez, Nelson Martins, Laura Mauring, Martin McKibbin, Terri L. McLaren, Isabelle Meunier, Michel Michaelides, José M. Millán, Kei Mizobuchi, Rajarshi Mukherjee, Zoltán Zsolt Nagy, Kornelia Neveling, Monika Ołdak, Michiel Oorsprong, Yang Pan, Anastasia Papachristou, Antonio Percesepe, Maximilian Pfau, Eric A. Pierce, Emily Place, Raj Ramesar, Francis Ramond, Florence Andrée Rasquin, Gillian I. Rice, Lisa Roberts, María Rodríguez-Hidalgo, Javier Ruiz-Ederra, Ataf H. Sabir, Ai Fujita Sajiki, Ana Isabel Sánchez-Barbero, Asodu Sandeep Sarma, Riccardo Sangermano, Cristina M. Santos, Margherita Scarpato, Hendrik P. N. Scholl, Dror Sharon, Sabrina G. Signorini, Francesca Simonelli, Ana Berta Sousa, Maria Stefaniotou, Kari Stefansson, Katarina Stingl, Akiko Suga, Patrick Sulem, Lori S. Sullivan, Viktória Szabó, Jacek P. Szaflik, Gita Taurina, Alberta A. H. J. Thiadens, Carmel Toomes, Viet H. Tran, Miltiadis K. Tsilimbaris, Pavlina Tsoka, Veronika Vaclavik, Marie Vajter, Sandra Valeina, Enza Maria Valente, Casey Valentine, Rebeca Valero, Sophie Valleix, Joseph van Aerschot, L. Ingeborgh van den Born, Mattias Van Heetvelde, Virginie J. M. Verhoeven, Andrea L. Vincent, Andrew R. Webster, Laura Whelan, Bernd Wissinger, Georgia G. Yioti, Kazutoshi Yoshitake, Juan C. Zenteno, Roberta Zeuli, Theresia Zuleger, Chaim Landau, Allan I. Jacob, Siying Lin, Frans P. M. Cremers, Winston Lee, Jamie M. Ellingford, David Stanek, Susanne Roosing and Carlo Rivolta
Nature Genet. 2026 Jan 09; doi: 10.1038/s41588-025-02451-4.
ABSTRACT
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.
