De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

作者：Mathieu Quinodoz, Kim Rodenburg, Zuzana Cvačková, Karolina Kamińska, 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, Alaa AlTalbishi, Sten Andréasson, Georg Ansari, Gavin Arno, Galuh Astuti, Carmen Ayuso, Radha Ayyagari, Sandro Banfi, Eyal Banin, Mirella Telles Salgueiro Barboni, Miriam Bauwens, Tamar Ben‐Yosef, David G. Birch, Pooja Biswas, Fiona Blanco‐Kelly, Béatrice Bocquet, Camiel J. F. Boon, Kari E. H. Branham, Alexis Ceecee Britten‐Jones, Kinga M. Bujakowska, Elizabeth L. Cadena, Giacomo Calzetti, Francesca Cancellieri, Luca Cattaneo, Peter Charbel Issa, Naomi Chadderton, Luísa Coutinho Santos, Stephen P. Daiger, Elfride De Baere, Berta de la Cerda, John N. De Roach, Julie De Zaeytijd, Ronny C. Derks, Claire‐Marie Dhaenens, Ľubica Ďuďáková, Jacque L. Duncan, Gwyneth Jane Farrar, Nicolas Feltgen, Lidia Fernández‐Caballero, Juliana Maria Ferraz Sallum, Simone Gana, Alejandro Garanto, Jessica C. Gardner, Christian Gilissen, Kensuke Goto, Roser Gonzàlez‐Duarte, Sam Griffiths‐Jones, Tobias B. Haack, Lonneke Haer‐Wigman, Alison J. Hardcastle, Takaaki Hayashi, Elise Héon, Alexander Hoischen, Josephine Prener Holtan, Carel B. Hoyng, Manuel Benjamin B. Ibanez, Chris F. Inglehearn, Takeshi Iwata, Kaylie Webb-Jones, Vasiliki Kalatzis, Smaragda Kamakari, Marianthi Karali, Ulrich Kellner, Krisztina Knézy, Caroline C. W. Klaver, Robert K. Koenekoop, Susanne Kohl, Taro Kominami, Laura Kuehlewein, Tina M. Lamey, Bart Peter Leroy, María Pilar Martín-Gutiérrez, Nelson Martins, Laura Mauring, Rina Leibu, Siying Lin, Petra Lišková, Irma López, Víctor Rodríguez, Omar A. Mahroo, Gaël Manès, Martin McKibbin, Terri L. McLaren, Isabelle Meunier, Michel Michaelides, José María 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, Florence Rasquin, Gillian Rice, Lisa J. Roberts, María Rodríguez-Hidalgo, Javier Ruiz‐Ederra, Ataf Hussain Sabir, Ai Fujita Sajiki, Ana Isabel Sánchez-Barbero, Asodu Sandeep Sarma, Riccardo Sangermano, Cristina Santos, Margherita Scarpato, Hendrik P. N. Scholl, Dror Sharon, Sabrina Giovanna Signorini, Francesca Simonelli, Ana Berta Sousa, Maria I. Stefaniotou, Katarína Štingl, Akiko Suga, Lori S. Sullivan, Viktória Szabó, Jacek Paweł Szaflik, Gita Tauriņa, Carmel Toomes, Hoai Viet Tran, Miltiadis K. Tsilimbaris, Pavlina Tsoka, Veronika Vaclavik, Marie Vajter, Sandra Valeiņa, Enza Maria Valente, Casey Valentine, Rebeca Valero, Joseph Van Aerschot, L. Ingeborgh van den Born, Andrew R. Webster, Laura Whelan, Bernd Wissinger, Georgia G. Yioti, Kazutoshi Yoshitake, Juan Carlos Zenteno, Roberta Zeuli, Theresia Zuleger, Chaim Landau, Allan I. Jacob, Frans P.M. Cremers, Winston Lee, Jamie M. Ellingford, David Staněk, Carlo Rivolta, Susanne Roosing · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.01.06.24317169 · 被引用次数：15 · 研究领域：Advanced biosensing and bioanalysis techniques、RNA regulation and disease、Cytomegalovirus and herpesvirus research

ABSTRACT The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders...