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

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.

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Publication Details

Journal
Nature Genetics
Published
2026-01-01
DOI
https://doi.org/10.1038/s41588-025-02451-4
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
44.47

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article

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

Ai Fujita Sajiki, Manuel Benjamin B. Ibanez, Kinga M. Bujakowska, Riccardo Sangermano et al.
2 citations
Nature Genetics
RNA Research and Splicing
44.47
article

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

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

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.

Nature GeneticsVol. 58(1)
Semmelweis University (HU), Jikei University School of Medicine (JP), University of Parma (IT), Oslo University Hospital (NO), Massachusetts Eye and Ear Infirmary (US), Hôpital Necker-Enfants Malades (FR), University of Leeds (GB), St Thomas' Hospital (GB), deCODE Genetics (Iceland) (IS), NewYork–Presbyterian Hospital (US), Harvard University (US), University of Lisbon (PT), University of Crete (GR), Radboud University Nijmegen (NL), University of Leicester (GB), University of Auckland (NZ), Inserm (FR), University of Cape Town (ZA), University of Iceland (IS), The University of Melbourne (AU), University of the Basque Country (ES), Technion – Israel Institute of Technology (IL), University of California, San Francisco (US), King's College London (GB), University of Basel (CH), Lund University (SE), University of Ioannina (GR), University of Campania "Luigi Vanvitelli" (IT), Université de Montpellier (FR), Czech Academy of Sciences (CZ), Université Paris Cité (FR), Trinity College Dublin (IE), Charles University (CZ), Université de Lille (FR), University of Cambridge (GB), University of Pavia (IT), Medical University of Warsaw (PL), University of Michigan (US), Singapore National Eye Center (SG), Leeds Teaching Hospitals NHS Trust (GB), Columbia University Irving Medical Center (US), Africa Center (US), Hadassah Medical Center (IL), Montreal Children's Hospital (CA), Leiden University Medical Center (NL), Institut Pasteur de Lille (FR), Ghent University Hospital (BE), Rambam Health Care Campus (IL), Hospital for Sick Children (CA), St James's University Hospital (GB), Instituto de Salud Carlos III (ES), Erasmus MC (NL), Erasmus Hospital (BE), Sir Charles Gairdner Hospital (AU), Makati Medical Center (PH), Tartu University Hospital (EE), Radboud University Medical Center (NL), University of Manchester (GB), St John of Jerusalem Eye Hospital Group (IL), Australian College of Optometry (AU), Ghent University (BE), Dublin Business School (IE), University of California San Diego (US), Institut Necker Enfants Malades (FR), Vitreous Retina Macula Consultants of New York (US), Hôpital Ophtalmique Jules-Gonin (CH), East Avenue Medical Center (PH), Centre de Recherche des Cordeliers (FR), Hôpital Cochin (FR), Manchester University NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Montpellier (FR), Tokyo Medical Center (JP), Helios Hospital Siegburg (DE), DIAKO (DE), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), Vision Eye Institute (AU), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Cell and Gene Therapy Catapult (GB), St Mary's Hospital (GB), Radboud Institute for Molecular Life Sciences (NL), Neurological Institute of Athens (GR), Centre for Biomedical Network Research on Rare Diseases (ES), Children's Clinical University Hospital (LV), Singapore Eye Research Institute (SG), Rotterdam Eye Hospital (NL), Centro Hospitalar de Lisboa Ocidental (PT), University Children's Hospital Tübingen (DE), Duke-NUS Medical School (SG), Retina Foundation of the Southwest (US), Fondation de Rothschild (FR), Hospital Universitario Fundación Jiménez Díaz (ES), Institute of Ophthalmology (MX), Institute of Molecular Genetics (RU), Institute for Neurosciences of Montpellier (FR), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Genomics England (GB), STZ eyetrial (DE), Oxford University Hospitals NHS Trust (GB), Greenwood Genetic Center (US), Hospital de Santa Maria (PT), Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES), Moorfields Eye Hospital (GB), Genomics (United Kingdom) (GB), Amsterdam University Medical Centers (NL), Telethon Institute Of Genetics And Medicine (IT), Birmingham Women’s and Children’s NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Saint-Étienne (FR), General University Hospital in Prague (CZ), Institute of Molecular and Clinical Ophthalmology Basel (CH), Instituto de Investigación Sanitaria La Fe (ES), Hôpital Broussais (FR), University College London (GB), University of Warsaw (PL), University of Tartu (EE), New York University (US), Nagoya University (JP), Technical University of Munich (DE), Universidad Autónoma de Madrid (ES), Universitat de Barcelona (ES), Jewish Hospital (US), Medical University of Vienna (AT), Columbia University (US), University of Birmingham (GB), University of Tübingen (DE), Universidade Nova de Lisboa (PT), Universidade Federal de São Paulo (BR), Universidad Nacional Autónoma de México (MX), The University of Texas Health Science Center at Houston (US), University of Lausanne (CH), KU Leuven (BE)
National Science Foundation, Research to Prevent Blindness, Velux Stiftung, Massachusetts Eye and Ear, Univerzita Karlova v Praze, Universität Basel, New York Eye and Ear Infirmary of Mount Sinai, Wellcome Trust, Hadassah Medical Organization, University of Texas Health Science Center at Houston, UK Research and Innovation, Université de Lille, Duke-NUS Medical School, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University of Leicester, University College London, University of Oxford, University of Manchester, University of Leeds, Singapore Eye Research Institute, Trinity College Dublin, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universiteit Leiden, University of Melbourne, Radboud Universiteit, Semmelweis Egyetem, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Generalitat Valenciana, Universitair Ziekenhuis Gent, Hebrew University of Jerusalem, Akademie Věd České Republiky, Universiteit Gent, Universidad Autónoma de Madrid, Ministerio de Ciencia e Innovación, Leids Universitair Medisch Centrum, Universidade de São Paulo, Technische Universität München, Universitat de Barcelona, Oxford University Hospitals NHS Foundation Trust, Radboud Universitair Medisch Centrum, Technion-Israel Institute of Technology, Université de Montpellier, Oogfonds, Assistance publique-Hôpitaux de Paris, Algemene Nederlandse Vereniging ter voorkoming van Blindheid, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blinden-Penning, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden, Moorfields Eye Hospital NHS Foundation Trust, Všeobecná Fakultní Nemocnice v Praze, Ústav Molekulární Genetiky, Akademie Věd České Republiky, National Institutes of Health, Directorate for Biological Sciences, University of California, San Diego, University of California, San Francisco, Irving Medical Center, Columbia University, School of Public Health, University of Texas Health Science Center at Houston, NYU Grossman School of Medicine, lékařská fakulta Univerzity Karlovy, Medical Research Council, UCL Institute of Ophthalmology, University College London, Instituto de Salud Carlos III, European Regional Development Fund, National Cancer Institute, Institute of Genetics
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RNA Research and Splicing
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