Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders

• 成果类型: Article
• 署名作者: De Jonghe, Joachim; Kim, Hyung Chul; Adedeji, Ayanfeoluwa; Leitao, Elsa; Dawes, Ruebena; Kajba, Christina M.; Cogne, Benjamin; Chen, Yuyang; Blakes, Alexander J. M.; Simons, Cas; Rius, Rocio; Alvi, Javeria R.; Amblard, Florence; Austin-Tse, Christina; Baer, Sarah; Balton, Elsa V.; Blanc, Pierre; Calame, Daniel G.; Coutton, Charles; Cunningham, Chloe A.; Dargie, Nitsuh; Dipple, Katrina M.; Du, Haowei; El Chehadeh, Salima; Glass, Ian; Gleeson, Joseph G.; Grunewald, Olivier; Gueguen, Paul; Harbuz, Radu; Jacquemont, Marie-Line; Leventer, Richard J.; Marijon, Pierre; Messaoud, Olfa; Sultan, Tipu; Thauvin, Christel; Vincent-Delorme, Catherine; Yilmaz Gulec, Elif; Thevenon, Julien; Mendez, Rodrigo; MacArthur, Daniel G.; Depienne, Christel; Nava, Caroline; Whiffin, Nicola; Findlay, Gregory M.
• 署名单位: Francis Crick Institute; University of Oxford; University of Oxford; Wellcome Centre for Human Genetics; University of London; University College London; University of Duisburg Essen; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Nantes Universite; CHU de Nantes; Nantes Universite; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); CHU de Nantes; University of Manchester; Garvan Institute of Medical Research; Murdoch Children's Research Institute; CHU Grenoble Alpes; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; CHU Strasbourg; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Washington; University of Washington Seattle; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Murdoch Children's Research Institute; Victorian Clinical Genetics Services; University of Melbourne; University of Washington; University of Washington Seattle; Baylor College of Medicine; Universites de Strasbourg Etablissements Associes; CHU Strasbourg; Universite de Strasbourg; Universites de Strasbourg Etablissements Associes; Universite de Lorraine; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Strasbourg; University of California System; University of California San Diego; Universite de Lille; Institut National de la Sante et de la Recherche Medicale (Inserm); CHU Lille; Universite de Lille; CHU Lille; CHU Tours; Universite de Tours; CHU Tours; Royal Children's Hospital Melbourne; Harvard University; Harvard Medical School; Universite Bourgogne Europe; CHU Dijon Bourgogne; Universite Bourgogne Europe; Institut Agro; Institut Agro Dijon; CHU Dijon Bourgogne; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Bourgogne Europe; Institut Agro; Institut Agro Dijon; Universite de Lille; CHU Lille; Istanbul Medeniyet University; Stanford University; Assistance Publique Hopitaux Paris (APHP); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; Hopital Universitaire Pitie-Salpetriere - APHP
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10334-9
• 发表日期: 2026-06-11
• 关键词: rna; variants; protein

摘要

Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome3. ReNU syndrome variants disrupt spliceosome function and alter 5 ' splice site selection1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants' effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development.