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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

The Journal of clinical investigation

Authors: Dong Li, Qin Wang, Allan Bayat, Mark R Battig, Yijing Zhou, Daniëlle Gm Bosch, Gijs van Haaften, Leslie Granger, Andrea K Petersen, Luis A Pérez-Jurado, Gemma Aznar-Laín, Anushree Aneja, Miroslava Hancarova, Sarka Bendova, Martin Schwarz, Radka Kremlíková Pourová, Zdenek Sedlacek, Beth A Keena, Michael E March, Cuiping Hou, Nora O'Connor, Elizabeth J Bhoj, Margaret H Harr, Gabrielle Lemire, Kym M Boycott, Meghan C Towne, Megan Li, Mark Tarnopolsky, Lauren Brady, Michael J Parker, Hanna Faghfoury, Lea Kristin Parsley, Emanuele Agolini, Maria Lisa Dentici, Antonio Novelli, Meredith S Wright, Rachel Palmquist, Khanh Lai, Marcello Scala, Pasquale Striano, Michele Iacomino, Federico Zara, Annina Cooper, Timothy J Maarup, Melissa Byler, Robert Roger Lebel, Tugce B Balci, Raymond J Louie, Michael J Lyons, Jessica Douglas, Catherine B Nowak, Alexandra Afenjar, Juliane Hoyer, Boris Keren, Saskia M Maas, Mahdi M Motazacker, Julian A Martinez-Agosto, Ahna M Rabani, Elizabeth M McCormick, Marni Falk, Sarah M Ruggiero, Ingo Helbig, Rikke S Møller, Lino Tessarollo, Francesco Tomassoni-Ardori, Mary Ellen Palko, Tzung-Chien Hsieh, Peter M Krawitz, Mythily Ganapathi, Bruce D Gelb, Vaidehi Jobanputra, Ashley Wilson, John Greally, Sébastien Jacquemont, Khadijé Jizi, Bruel Ange-Line, Chloé Quelin, Vinod K Misra, Erika Chick, Corrado Romano, Donatella Greco, Alessia Arena, Manuela Morleo, Vincenzo Nigro, Rie Seyama, Yuri Uchiyama, Naomichi Matsumoto, Ryoji Taira, Katsuya Tashiro, Yasunari Sakai, Gökhan Yigit, Bernd Wollnik, Michael Wagner, Barbara Kutsche, Anna Ce Hurst, Michelle L Thompson, Ryan J Schmidt, Linda M Randolph, Rebecca C Spillmann, Vandana Shashi, Edward J Higginbotham, Dawn Cordeiro, Amanda Carnevale, Gregory Costain, Tayyaba Khan, Benoît Funalot, Frederic Tran Mau-Them, Luis Fernandez Garcia Moya, Sixto García-Miñaúr, Matthew Osmond, Lauren Chad, Nada Quercia, Diana Carrasco, Chumei Li, Amarilis Sanchez-Valle, Meghan Kelley, Mathilde Nizon, Brynjar O Jensson, Patrick Sulem, Kari Stefansson, Svetlana Gorokhova, Tiffany Busa, Marlène Rio, Hamza Hadj Abdallah, Marion Lesieur-Sebellin, Jeanne Amiel, Véronique Pingault, Sandra Mercier, Marie Vincent, Christophe Philippe, Clemence Fatus-Fauconnier, Kathryn Friend, Rebecca K Halligan, Sunita Biswas, Jane Mr Rosser, Cheryl Shoubridge, Mark A Corbett, Christopher Barnett, Jozef Gecz, Kathleen A Leppig, Anne Slavotinek, Carlo Marcelis, Rolph Pfundt, Bert Ba de Vries, Marjon A van Slegtenhorst, Alice S Brooks, Benjamin Cogne, Thomas Rambaud, Zeynep Tümer, Elaine H Zackai, Naiara Akizu, Yuanquan Song, Hakon Hakonarson

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

PMID: 37962958

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