. 2026 Jan;58(1):169-179.

doi: 10.1038/s41588-025-02451-4. Epub 2026 Jan 9.

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

Mathieu Quinodoz^#^{1

2

3}, Kim Rodenburg^#⁴, Zuzana Cvackova⁵, Karolina Kaminska^{1

2}, Suzanne E de Bruijn^{4

6}, Ana Belén Iglesias-Romero^{1

2}, Erica G M Boonen^{4

7}, Mukhtar Ullah¹, Nick Zomer⁴, Marc Folcher^{1

2}, Jacques Bijon^{8

9}, Lara K Holtes⁴, Stephen H Tsang^{10

11}, Zelia Corradi⁴, K Bailey Freund^{8

12}, Stefanida Shliaga⁴, Daan M Panneman⁴, Rebekkah J Hitti-Malin⁴, Manir Ali¹³, Ala'a AlTalbishi¹⁴, Sten Andréasson¹⁵, Georg Ansari², Gavin Arno^{16

17

18}, Galuh D N Astuti⁴, Carmen Ayuso^{19

20}, Radha Ayyagari²¹, Sandro Banfi^{22

23}, Eyal Banin²⁴, Tahsin Stefan Barakat²⁵, Mirella T S Barboni²⁶, Miriam Bauwens^{27

28}, Tamar Ben-Yosef²⁹, Virginie Bernard³⁰, David G Birch³¹, Pooja Biswas²¹, Fiona Blanco-Kelly^{19

20}, Beatrice Bocquet^{32

33}, Camiel J F Boon^{34

35}, Kari Branham³⁶, Dominique Bremond-Gignac^{37

38}, Alexis Ceecee Britten-Jones³⁹, Kinga M Bujakowska⁴⁰, Cyril Burin des Roziers^{38

41

42}, Elizabeth L Cadena⁴³, Giacomo Calzetti^{44

45}, Francesca Cancellieri^{1

2}, Luca Cattaneo⁴⁶, Naomi Chadderton⁴⁷, Peter Charbel Issa^{48

49}, Luísa Coutinho-Santos⁵⁰, Stephen P Daiger⁴³, Elfride De Baere^{27

28}, Marieke De Bruyne^{27

28}, Berta de la Cerda⁵¹, John N De Roach⁵², Julie De Zaeytijd^{53

54}, Ronny Derks⁴, Claire-Marie Dhaenens⁵⁵, Lubica Dudakova⁵⁶, Jacque L Duncan⁵⁷, G Jane Farrar⁴⁷, Nicolas Feltgen², Beau J Fenner^{58

59

60}, Lidia Fernández-Caballero^{19

20}, Juliana M Ferraz Sallum⁶¹, Simone Gana⁴⁶, Alejandro Garanto^{4

62}, Jessica C Gardner¹⁷, Christian Gilissen⁴, Roser Gonzàlez-Duarte⁶³, Kensuke Goto⁶⁴, Sam Griffiths-Jones⁶⁵, Tobias B Haack^{66

67

68}, Lonneke Haer-Wigman⁴, Alison J Hardcastle¹⁷, Takaaki Hayashi⁶⁹, Elise Héon⁷⁰, Lies H Hoefsloot²⁵, Alexander Hoischen^{4

71}, Josephine P Holtan⁷², Carel B Hoyng⁷³, Manuel Benjamin B Ibanez 4th^{74

75}, Chris F Inglehearn¹³, Takeshi Iwata⁷⁶, Brynjar O Jensson⁷⁷, Kaylie Jones³¹, Vasiliki Kalatzis^{32

33}, Smaragda Kamakari⁷⁸, Marianthi Karali^{22

79}, Ulrich Kellner⁸⁰, Caroline C W Klaver^{73

81}, Krisztina Knézy²⁶, Robert K Koenekoop⁸², Susanne Kohl⁸³, Taro Kominami⁶⁴, Laura Kühlewein⁸⁴, Tina M Lamey⁵², Rina Leibu⁸⁵, Bart P Leroy^{27

53

54}, Petra Liskova^{56

86}, Irma Lopez⁸², Victor R de J López-Rodríguez⁸⁷, Quinten Mahieu^{27

28}, Omar A Mahroo^{17

18

88

89}, Gaël Manes³², Luke Mansard^{30

32

90}, M Pilar Martín-Gutiérrez⁹¹, Nelson Martins^{27

28}, Laura Mauring^{92

93

94}, Martin McKibbin^{13

95}, Terri L McLaren⁵², Isabelle Meunier^{32

33}, Michel Michaelides^{17

18}, José M Millán⁹⁶, Kei Mizobuchi⁶⁹, Rajarshi Mukherjee⁹⁵, Zoltán Zsolt Nagy²⁶, Kornelia Neveling⁴, Monika Ołdak⁹⁷, Michiel Oorsprong⁴, Yang Pan⁷⁶, Anastasia Papachristou⁹⁸, Antonio Percesepe⁹⁹, Maximilian Pfau², Eric A Pierce⁴⁰, Emily Place⁴⁰, Raj Ramesar¹⁰⁰, Francis Ramond^{30

101}, Florence Andrée Rasquin¹⁰², Gillian I Rice⁶⁵, Lisa Roberts¹⁰⁰, María Rodríguez-Hidalgo^{103

104}, Javier Ruiz-Ederra^{103

105}, Ataf H Sabir^{106

107}, Ai Fujita Sajiki⁶⁴, Ana Isabel Sánchez-Barbero^{19

20}, Asodu Sandeep Sarma²⁴, Riccardo Sangermano⁴⁰, Cristina M Santos^{50

108}, Margherita Scarpato²², Hendrik P N Scholl^{109

110

111}, Dror Sharon²⁴, Sabrina G Signorini¹¹², Francesca Simonelli⁷⁹, Ana Berta Sousa^{113

114}, Maria Stefaniotou¹¹⁵, Kari Stefansson^{77

116}, Katarina Stingl⁸⁴, Akiko Suga⁷⁶, Patrick Sulem⁷⁷, Lori S Sullivan⁴³, Viktória Szabó²⁶, Jacek P Szaflik^{117

118}, Gita Taurina¹¹⁹, Alberta A H J Thiadens⁸¹, Carmel Toomes¹³, Viet H Tran^{120

121}, Miltiadis K Tsilimbaris⁹⁸, Pavlina Tsoka⁹⁸, Veronika Vaclavik¹²⁰, Marie Vajter^{56

86}, Sandra Valeina¹²², Enza Maria Valente^{46

123}, Casey Valentine¹⁰⁰, Rebeca Valero⁶³, Sophie Valleix^{38

41

42}, Joseph van Aerschot¹²⁴, L Ingeborgh van den Born⁷, Mattias Van Heetvelde^{27

28}, Virginie J M Verhoeven^{25

81}, Andrea L Vincent¹²⁵, Andrew R Webster^{17

18}, Laura Whelan^{47

126

127}, Bernd Wissinger⁸³, Georgia G Yioti¹¹⁵, Kazutoshi Yoshitake⁷⁶, Juan C Zenteno^{87

128}, Roberta Zeuli²², Theresia Zuleger⁶⁶, Chaim Landau¹²⁹, Allan I Jacob¹³⁰, Siying Lin^{18

131

132}, Frans P M Cremers⁴, Winston Lee¹³³, Jamie M Ellingford^{65

134}, David Stanek⁵, Susanne Roosing¹³⁵, Carlo Rivolta^{1

2

3}

Affiliations

¹ Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
² Department of Ophthalmology, University of Basel, Basel, Switzerland.
³ Department of Genetics, Genomics and Cancer Sciences, University of Leicester, Leicester, UK.
⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Laboratory of RNA Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
⁶ Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ The Rotterdam Eye Hospital, Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands.
⁸ Vitreous Retina Macula Consultants of New York, New York, NY, USA.
⁹ Department of Ophthalmology, Rothschild Foundation Hospital, Paris, France.
¹⁰ Departments of Ophthalmology, Pathology & Cell Biology, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons Columbia University Irving Medical Center, New York, NY, USA.
¹¹ Edward S. Harkness Eye Institute, Jonas Children's Vision Care (JCVC), Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York, NY, USA.
¹² Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA.
¹³ Division of Molecular Medicine, Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, UK.
¹⁴ Molecular Biology Research Unit, St John Eye Hospital Group, Jerusalem, Palestine.
¹⁵ Department of Ophthalmology, University Hospital of Lund, Lund, Sweden.
¹⁶ JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, USA.
¹⁷ UCL Institute of Ophthalmology, University College London, London, UK.
¹⁸ National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital, London, UK.
¹⁹ Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
²⁰ Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²¹ Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
²² Medical Genetics, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
²³ Genomic Medicine, Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
²⁴ Hadassah Medical Center, Division of Ophthalmology, The Hebrew University of Jerusalem, Jerusalem, Israel.
²⁵ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
²⁶ Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
²⁷ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
²⁸ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
²⁹ Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
³⁰ GCS Auragen, Plan France Medecine Genomique, Lyon, France.
³¹ Retina Foundation of the Southwest, Dallas, TX, USA.
³² Institute for Neurosciences of Montpellier (INM), Montpellier University, INSERM, Montpellier, France.
³³ National Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Montpellier, France.
³⁴ Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
³⁵ Department of Ophthalmology, Amsterdam University Medical Center, Amsterdam, the Netherlands.
³⁶ Department of Ophthalmology and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Ophthalmology, University Hospital Necker Enfants Malades, APHP, Paris Cité University, Paris, France.
³⁸ UMRS1138, Centre de Recherche des Cordeliers, Université Paris Cité, INSERM, Paris, France.
³⁹ Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁰ Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
⁴¹ Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, AP-HP Centre Université Paris Cité, Paris, France.
⁴² Laboratoire de Biologie Médicale SeqOIA, Site Broussais, Paris, France.
⁴³ Department of Epidemiology and Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁴ Vista Vision Eye Clinic, Brescia, Italy.
⁴⁵ Clinical Translation Group, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
⁴⁶ Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy.
⁴⁷ Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.
⁴⁸ Department of Ophthalmology, TUM University Hospital, School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁴⁹ Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁵⁰ Serviço de Oftalmologia, Instituto de Oftalmologia Dr. Gama Pinto, Lisboa, Portugal.
⁵¹ Department of Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre, CABIMER, Seville, Spain.
⁵² Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
⁵³ Department of Head and Skin, Ghent University, Ghent, Belgium.
⁵⁴ Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
⁵⁵ Université de Lille, INSERM U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France.
⁵⁶ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
⁵⁷ Department of Ophthalmology, University of California, San Francisco, Wayne and Gladys Valley Center for Vision, San Francisco, CA, USA.
⁵⁸ Department of Medical Retina, Singapore National Eye Centre, Singapore, Singapore.
⁵⁹ Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
⁶⁰ Singapore Eye Research Institute, Singapore, Singapore.
⁶¹ Department of Ophthalmology, Federal University of São Paulo, UNIFESP, São Paulo, Brazil.
⁶² Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
⁶³ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁶⁴ Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁵ School of Biological Sciences, Division of Evolution, Infection, and Genomics, The University of Manchester, Manchester, UK.
⁶⁶ Institute for Medical Genetics and Applied Genomics, University of Tübingen, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany.
⁶⁷ Center for Rare Disease, University of Tübingen, Tübingen, Germany.
⁶⁸ Genomics for Health in Africa (GHA), Africa-Europe Cluster of Research Excellence (CoRE), Ghana, South Africa.
⁶⁹ Department of Ophthalmology, The Jikei University School of Medicine, Minato-ku, Japan.
⁷⁰ Department of Ophthalmology and Vision Sciences, Ocular Genetics Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷¹ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷² Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
⁷³ Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷⁴ Department of Ophthalmology, Section of Pediatric Ophthalmology, Strabismus, and Ocular Genetics, DOH Eye Center, East Avenue Medical Center, Quezon City, Philippines.
⁷⁵ Section of Pediatric Ophthalmology, Strabismus, and Ocular Genetics, Makati Medical Center, Makati City, Philippines.
⁷⁶ Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan.
⁷⁷ deCODE genetics, Amgen Inc., Reykjavik, Iceland.
⁷⁸ Department of Inherited Retinal Dystrophies, Ophthalmic Genetics Group, OMMA, Ophthalmological Institute of Athens, Athens, Greece.
⁷⁹ Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁸⁰ Center for Rare Retinal Diseases, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Siegburg, Germany.
⁸¹ Department of Ophthalmology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁸² Department of Pediatric Surgery, Division of Pediatric Ophthalmology, Montreal Children's Hospital, McGill University Health Center (MUHC), Montreal, Quebec, Canada.
⁸³ Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.
⁸⁴ University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.
⁸⁵ Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel.
⁸⁶ Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
⁸⁷ Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.
⁸⁸ Section of Ophthalmology, King's College London, St. Thomas' Hospital Campus, London, UK.
⁸⁹ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
⁹⁰ Molecular Genetics Laboratory, Montpellier University, CHU Montpellier, Montpellier, France.
⁹¹ Department of Ophthalmology, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
⁹² Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁹³ Eye Clinic, Tartu University Hospital, Tartu, Estonia.
⁹⁴ Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
⁹⁵ Department of Ophthalmology, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK.
⁹⁶ Instituto de Investigación Sanitaria La Fe (IIS La Fe) and CIBERER, Valencia, Spain.
⁹⁷ Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland.
⁹⁸ Department of Ophthalmology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
⁹⁹ Department of Medicine and Surgery, Medical Genetics, University of Parma, Parma, Italy.
¹⁰⁰ UCT/MRC Precision and Genomic Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
¹⁰¹ Department of Medical Genetics, Saint-Etienne University Hospital, Saint-Etienne, France.
¹⁰² Department of Ophthalmology, HUB-Erasme Hospital, Brussels, Belgium.
¹⁰³ Department of Neuroscience, Biodonostia Health Research Institute, Donostia-San Sebastián, Spain.
¹⁰⁴ Department of Genetic, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
¹⁰⁵ Department of Ophthalmology, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
¹⁰⁶ West Midlands Clinical Genetics Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
¹⁰⁷ College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
¹⁰⁸ iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal.
¹⁰⁹ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
¹¹⁰ Pallas Kliniken AG, Pallas Klinik Zürich, Zürich, Switzerland.
¹¹¹ European Vision Institute, Basel, Switzerland.
¹¹² Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.
¹¹³ Department of Medical Genetics, ULS Santa Maria, Lisboa, Portugal.
¹¹⁴ Laboratory of Basic Immunology, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
¹¹⁵ Department of Ophthalmology, School of Medicine, University of Ioannina, Ioannina, Greece.
¹¹⁶ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
¹¹⁷ Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
¹¹⁸ SPKSO Ophthalmic University Hospital in Warsaw, Warsaw, Poland.
¹¹⁹ Medical Genetics and Prenatal Diagnostics Clinic, Children's Clinical University Hospital, Riga, Latvia.
¹²⁰ Department of Ophthalmology; Oculogenetics Unit, Jules Gonin University Hospital; University of Lausanne, Lausanne, Switzerland.
¹²¹ Centre for Gene Therapy & Regenerative Medicine, King's College London, London, UK.
¹²² Eye Disease Clinic, Children's University Hospital Riga, Riga, Latvia.
¹²³ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹²⁴ Department of Ophthalmology, Pediatric Ophthalmology and Ophthalmogenetics, University Hospitals Leuven, Leuven, Belgium.
¹²⁵ Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.
¹²⁶ School of Pharmacy and Biomolecular Sciences (PBS), RCSI University of Medicine and Health Sciences, Dublin, Ireland.
¹²⁷ FutureNeuro Research Ireland Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
¹²⁸ Department of Biochemistry, Faculty of Medicine, UNAM, Mexico City, Mexico.
¹²⁹ Bonei Olam - Center for Rare Jewish Genetic Diseases, Brooklyn, NY, USA.
¹³⁰ Physicians Dialysis, Miami, FL, USA.
¹³¹ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
¹³² Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
¹³³ Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA.
¹³⁴ Genomics England Ltd, London, UK.
¹³⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. susanne.roosing@radboudumc.nl.

^# Contributed equally.

PMID: 41513982
PMCID: PMC12807869
DOI: 10.1038/s41588-025-02451-4

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

Mathieu Quinodoz et al. Nat Genet. 2026 Jan.

. 2026 Jan;58(1):169-179.

doi: 10.1038/s41588-025-02451-4. Epub 2026 Jan 9.

Authors

Affiliations

¹ Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
² Department of Ophthalmology, University of Basel, Basel, Switzerland.
³ Department of Genetics, Genomics and Cancer Sciences, University of Leicester, Leicester, UK.
⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Laboratory of RNA Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
⁶ Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ The Rotterdam Eye Hospital, Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands.
⁸ Vitreous Retina Macula Consultants of New York, New York, NY, USA.
⁹ Department of Ophthalmology, Rothschild Foundation Hospital, Paris, France.
¹⁰ Departments of Ophthalmology, Pathology & Cell Biology, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons Columbia University Irving Medical Center, New York, NY, USA.
¹¹ Edward S. Harkness Eye Institute, Jonas Children's Vision Care (JCVC), Columbia University Irving Medical Center, New York-Presbyterian Hospital, New York, NY, USA.
¹² Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA.
¹³ Division of Molecular Medicine, Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, UK.
¹⁴ Molecular Biology Research Unit, St John Eye Hospital Group, Jerusalem, Palestine.
¹⁵ Department of Ophthalmology, University Hospital of Lund, Lund, Sweden.
¹⁶ JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, USA.
¹⁷ UCL Institute of Ophthalmology, University College London, London, UK.
¹⁸ National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital, London, UK.
¹⁹ Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
²⁰ Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²¹ Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
²² Medical Genetics, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
²³ Genomic Medicine, Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
²⁴ Hadassah Medical Center, Division of Ophthalmology, The Hebrew University of Jerusalem, Jerusalem, Israel.
²⁵ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
²⁶ Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
²⁷ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
²⁸ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
²⁹ Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
³⁰ GCS Auragen, Plan France Medecine Genomique, Lyon, France.
³¹ Retina Foundation of the Southwest, Dallas, TX, USA.
³² Institute for Neurosciences of Montpellier (INM), Montpellier University, INSERM, Montpellier, France.
³³ National Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Montpellier, France.
³⁴ Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
³⁵ Department of Ophthalmology, Amsterdam University Medical Center, Amsterdam, the Netherlands.
³⁶ Department of Ophthalmology and Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁷ Department of Ophthalmology, University Hospital Necker Enfants Malades, APHP, Paris Cité University, Paris, France.
³⁸ UMRS1138, Centre de Recherche des Cordeliers, Université Paris Cité, INSERM, Paris, France.
³⁹ Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁰ Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
⁴¹ Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, AP-HP Centre Université Paris Cité, Paris, France.
⁴² Laboratoire de Biologie Médicale SeqOIA, Site Broussais, Paris, France.
⁴³ Department of Epidemiology and Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁴ Vista Vision Eye Clinic, Brescia, Italy.
⁴⁵ Clinical Translation Group, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
⁴⁶ Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy.
⁴⁷ Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.
⁴⁸ Department of Ophthalmology, TUM University Hospital, School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁴⁹ Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁵⁰ Serviço de Oftalmologia, Instituto de Oftalmologia Dr. Gama Pinto, Lisboa, Portugal.
⁵¹ Department of Cell Therapy and Regenerative Medicine, Andalusian Molecular Biology and Regenerative Medicine Centre, CABIMER, Seville, Spain.
⁵² Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
⁵³ Department of Head and Skin, Ghent University, Ghent, Belgium.
⁵⁴ Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
⁵⁵ Université de Lille, INSERM U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France.
⁵⁶ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
⁵⁷ Department of Ophthalmology, University of California, San Francisco, Wayne and Gladys Valley Center for Vision, San Francisco, CA, USA.
⁵⁸ Department of Medical Retina, Singapore National Eye Centre, Singapore, Singapore.
⁵⁹ Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
⁶⁰ Singapore Eye Research Institute, Singapore, Singapore.
⁶¹ Department of Ophthalmology, Federal University of São Paulo, UNIFESP, São Paulo, Brazil.
⁶² Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
⁶³ Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
⁶⁴ Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁵ School of Biological Sciences, Division of Evolution, Infection, and Genomics, The University of Manchester, Manchester, UK.
⁶⁶ Institute for Medical Genetics and Applied Genomics, University of Tübingen, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany.
⁶⁷ Center for Rare Disease, University of Tübingen, Tübingen, Germany.
⁶⁸ Genomics for Health in Africa (GHA), Africa-Europe Cluster of Research Excellence (CoRE), Ghana, South Africa.
⁶⁹ Department of Ophthalmology, The Jikei University School of Medicine, Minato-ku, Japan.
⁷⁰ Department of Ophthalmology and Vision Sciences, Ocular Genetics Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷¹ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷² Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
⁷³ Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷⁴ Department of Ophthalmology, Section of Pediatric Ophthalmology, Strabismus, and Ocular Genetics, DOH Eye Center, East Avenue Medical Center, Quezon City, Philippines.
⁷⁵ Section of Pediatric Ophthalmology, Strabismus, and Ocular Genetics, Makati Medical Center, Makati City, Philippines.
⁷⁶ Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan.
⁷⁷ deCODE genetics, Amgen Inc., Reykjavik, Iceland.
⁷⁸ Department of Inherited Retinal Dystrophies, Ophthalmic Genetics Group, OMMA, Ophthalmological Institute of Athens, Athens, Greece.
⁷⁹ Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁸⁰ Center for Rare Retinal Diseases, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Siegburg, Germany.
⁸¹ Department of Ophthalmology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁸² Department of Pediatric Surgery, Division of Pediatric Ophthalmology, Montreal Children's Hospital, McGill University Health Center (MUHC), Montreal, Quebec, Canada.
⁸³ Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.
⁸⁴ University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.
⁸⁵ Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel.
⁸⁶ Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
⁸⁷ Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.
⁸⁸ Section of Ophthalmology, King's College London, St. Thomas' Hospital Campus, London, UK.
⁸⁹ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
⁹⁰ Molecular Genetics Laboratory, Montpellier University, CHU Montpellier, Montpellier, France.
⁹¹ Department of Ophthalmology, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
⁹² Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁹³ Eye Clinic, Tartu University Hospital, Tartu, Estonia.
⁹⁴ Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
⁹⁵ Department of Ophthalmology, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK.
⁹⁶ Instituto de Investigación Sanitaria La Fe (IIS La Fe) and CIBERER, Valencia, Spain.
⁹⁷ Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland.
⁹⁸ Department of Ophthalmology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
⁹⁹ Department of Medicine and Surgery, Medical Genetics, University of Parma, Parma, Italy.
¹⁰⁰ UCT/MRC Precision and Genomic Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
¹⁰¹ Department of Medical Genetics, Saint-Etienne University Hospital, Saint-Etienne, France.
¹⁰² Department of Ophthalmology, HUB-Erasme Hospital, Brussels, Belgium.
¹⁰³ Department of Neuroscience, Biodonostia Health Research Institute, Donostia-San Sebastián, Spain.
¹⁰⁴ Department of Genetic, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
¹⁰⁵ Department of Ophthalmology, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
¹⁰⁶ West Midlands Clinical Genetics Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
¹⁰⁷ College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
¹⁰⁸ iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal.
¹⁰⁹ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
¹¹⁰ Pallas Kliniken AG, Pallas Klinik Zürich, Zürich, Switzerland.
¹¹¹ European Vision Institute, Basel, Switzerland.
¹¹² Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.
¹¹³ Department of Medical Genetics, ULS Santa Maria, Lisboa, Portugal.
¹¹⁴ Laboratory of Basic Immunology, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
¹¹⁵ Department of Ophthalmology, School of Medicine, University of Ioannina, Ioannina, Greece.
¹¹⁶ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
¹¹⁷ Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
¹¹⁸ SPKSO Ophthalmic University Hospital in Warsaw, Warsaw, Poland.
¹¹⁹ Medical Genetics and Prenatal Diagnostics Clinic, Children's Clinical University Hospital, Riga, Latvia.
¹²⁰ Department of Ophthalmology; Oculogenetics Unit, Jules Gonin University Hospital; University of Lausanne, Lausanne, Switzerland.
¹²¹ Centre for Gene Therapy & Regenerative Medicine, King's College London, London, UK.
¹²² Eye Disease Clinic, Children's University Hospital Riga, Riga, Latvia.
¹²³ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹²⁴ Department of Ophthalmology, Pediatric Ophthalmology and Ophthalmogenetics, University Hospitals Leuven, Leuven, Belgium.
¹²⁵ Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.
¹²⁶ School of Pharmacy and Biomolecular Sciences (PBS), RCSI University of Medicine and Health Sciences, Dublin, Ireland.
¹²⁷ FutureNeuro Research Ireland Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
¹²⁸ Department of Biochemistry, Faculty of Medicine, UNAM, Mexico City, Mexico.
¹²⁹ Bonei Olam - Center for Rare Jewish Genetic Diseases, Brooklyn, NY, USA.
¹³⁰ Physicians Dialysis, Miami, FL, USA.
¹³¹ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
¹³² Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
¹³³ Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA.
¹³⁴ Genomics England Ltd, London, UK.
¹³⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. susanne.roosing@radboudumc.nl.

^# Contributed equally.

PMID: 41513982
PMCID: PMC12807869
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.

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Conflict of interest statement

Competing interests: The authors affiliated with deCODE genetics/Amgen Inc. (B.O.J., K. Stefansson, P.S.) are employed by the company. The other authors declare no competing interests.

Figures

**Fig. 1. Structure of the U4/U6 duplex and rare variants found in RP cases and controls (gnomAD).**
a, Two-dimensional structure of the U4/U6 duplex, with recurrent variants identified in RP cases (in red for U4 and in green for U6), all clustering within the three-way junction. Nucleotides affected by variants previously observed in NDD cases are underlined. b, Rare variants affecting *RNU4-1*, defined as AF < 0.1% in gnomAD v.4.1, identified in RP cases and in controls. c, Same as in b for *RNU4-2*, with recurrent pathogenic variants displayed in red. d, Same as b for all five *RNU6* paralogs combined, with recurrent causative variants displayed in green. Significant P values for variants enriched in RP cases versus controls from gnomAD are indicated (two-sided Fisher’s test with Bonferroni correction).

**Fig. 2. Three-dimensional structure, from cryo-electron microscopy (PDB 6QW6), of the U4/U6 duplex and its interactions with neighboring splicing factors.**
a, Naked U4/U6 pairing, showing the proximity of the causative variants identified (red and green). b, Same as in a with interacting PRPF proteins. c, Direct interactions of nucleotides of the U4/U6 duplex with PRPF31, via hydrogen bonds. d, Same as c but for PRPF3.

**Fig. 3. Expression and markers of transcriptional activity of *RNU4* and *RNU6* genes.**
a, Expression of *RNU4-1* and *RNU4-2* from RNA-seq of human donor choroid (n = 13), NSR (n = 4) and RPE (n = 16). For these boxplots, the tick line within boxes indicates the median (also expressed numerically), boxes represent the first and the third quartiles and whiskers indicate the largest observation smaller than or equal to the first quartile − 1.5 × IQR and the smallest observation greater than or equal to the third quartile + 1.5 × IQR. b, Same as in a for *RNU4* genes (*RNU4-1*, *RNU4-2* and pseudogenes) and for all *RNU6* genes (*RNU6-1*, *RNU6-2*, *RNU6-7*, *RNU6-8*, *RNU6-9* and pseudogenes). c, ATAC-seq and H3K27ac signals for *RNU4-1, RNU4-2*, *RNU4ATAC* (red) and 105 *RNU4* pseudogenes (black). d, Same as in c for five *RNU6* genes and *RNU6ATAC* (red), as well as for 1,312 *RNU6* pseudogenes (black). IQR, interquartile range.

**Fig. 4. Effects of RP variants in *RNU4-2* and *RNU6* on snRNP maturation.**
a,b, Immunoprecipitation of U4-MS2 (WT and variants) (a) and U6-MS2 (WT and variants) (b). snRNPs were immunoprecipitated via MS2-YFP by anti-GFP antibodies and co-precipitated proteins were detected by western blotting. The position of the MS2 loop (green) in snRNAs is indicated. Four independent experiments were quantified. Immunoprecipitated proteins are normalized to input and U4 or U6 WT controls. Middle bars indicate average values and error bars the s.e.m. Statistical significance was analyzed by the two-tailed unpaired t-test and the P values were adjusted using the Benjamini–Hochberg FDR method to control for false discoveries. P values ≤ 0.05 are indicated. Full-length blots and antibody validation are provided as Source Data. Ctrl, control; IP, immunoprecipitation; WT, wild type. Source data

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Update of

De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.
Quinodoz M, Rodenburg K, Cvackova Z, Kaminska K, de Bruijn SE, Iglesias-Romero AB, Boonen EGM, Ullah M, Zomer N, Folcher M, Bijon J, Holtes LK, Tsang SH, Corradi Z, Freund KB, Shliaga S, Panneman DM, Hitti-Malin RJ, Ali M, AlTalbishi A, Andréasson S, Ansari G, Arno G, Astuti GDN, Ayuso C, Ayyagari R, Banfi S, Banin E, Barboni MTS, Bauwens M, Ben-Yosef T, Birch DG, Biswas P, Blanco-Kelly F, Bocquet B, Boon CJF, Branham K, Britten-Jones AC, Bujakowska KM, Cadena EL, Calzetti G, Cancellieri F, Cattaneo L, Issa PC, Chadderton N, Coutinho-Santos L, Daiger SP, De Baere E, de la Cerda B, De Roach JN, De Zaeytijd J, Derks R, Dhaenens CM, Dudakova L, Duncan JL, Farrar GJ, Feltgen N, Fernández-Caballero L, Sallum JMF, Gana S, Garanto A, Gardner JC, Gilissen C, Goto K, Gonzàlez-Duarte R, Griffiths-Jones S, Haack TB, Haer-Wigman L, Hardcastle AJ, Hayashi T, Héon E, Hoischen A, Holtan JP, Hoyng CB, Ibanez MBB 4th, Inglehearn CF, Iwata T, Jones K, Kalatzis V, Kamakari S, Karali M, Kellner U, Knézy K, Klaver CCW, Koenekoop RK, Kohl S, Kominami T, Kühlewein L, Lamey TM, Leroy BP, Martín-Gutiérrez MP, Martins N, Mauring L, Leibu R, Lin S, Liskova P, Lopez I, López-Rodríguez VRJ, Mahroo OA, Manes G… See abstract for full author list ➔ Quinodoz M, et al. medRxiv [Preprint]. 2025 Jan 6:2025.01.06.24317169. doi: 10.1101/2025.01.06.24317169. medRxiv. 2025. Update in: Nat Genet. 2026 Jan;58(1):169-179. doi: 10.1038/s41588-025-02451-4. PMID: 39830270 Free PMC article. Updated. Preprint.

References

1. Verbakel, S. K. et al. Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res.66, 157–186 (2018). - DOI - PubMed
1. Peter, V. G. et al. The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. PNAS Nexus2, pgad043 (2023). - DOI - PMC - PubMed
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De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa

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

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Conflict of interest statement

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