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<p>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 <i>RNU4-2</i>, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in <i>RNU4-2</i> and in four <i>RNU6</i> paralogs (<i>RNU6-1</i>, <i>RNU6-2</i>, <i>RNU6-8</i> and <i>RNU6-9</i>), 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 (<i>PRPF3</i>, <i>PRPF8</i>, <i>PRPF31</i>), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in <i>RNU4-2</i> and <i>RNU6</i> 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 <i>RNU4-2</i>, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • 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,
  • Carlo Rivolta

摘要

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.