Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
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Li, Dong | Wang, Qin | Bayat, Allan | Battig, Mark R. | Zhou, Yijing | Bosch, Danielle G. M. | Haaften, Gijs, Van | Granger, Leslie | Petersen, Andrea K. | Perez-Jurado, Luis A. | Aznar-Lain, Gemma | Aneja, Anushree | Hancarova, Miroslava | Bendova, Sarka | Schwarz, Martin | Pourova, Radka Kremlikova | Sedlacek, Zdenek | Keena, Beth A. | March, Michael E. | Hou, Cuiping | O'Connor, Nora | Bhoj, Elizabeth J. | Harr, Margaret H. | Lemire, Gabrielle | Boycott, Kym M. | Towne, Meghan | Li, Megan | Tarnopolsky, Mark | Brady, Lauren | Parker, Michael J. | Faghfoury, Hanna | Parsley, Lea Kristin | Agolini, Emanuele | Dentici, Maria Lisa | Novelli, Antonio | Wright, Meredith | Palmquist, Rachel | Lai, Khanh | Scala, Marcello | Striano, Pasquale | Iacomino, Michele | Zara, Federico | Cooper, Annina | Maarup, Timothy J. | Byler, Melissa | Lebel, Robert Roger | Balci, Tugce B. | Louie, Raymond | Lyons, Michael | Douglas, Jessica | Nowak, Catherine | Afenjar, Alexandra | Hoyer, Juliane | Keren, Boris | Maas, Saskia M. | Motazacker, Mahdi M. | Martinez-Agosto, Julian A. | Rabani, Ahna M. | Mccormick, Elizabeth M. | Falk, Marni J. | Ruggiero, Sarah M. | Helbig, Ingo | Moller, Rikke S. | Tessarollo, Lino | Ardori, Francesco Tomassoni | Palko, Mary Ellen | Hsieh, Tzung-Chien | Krawitz, Peter M. | Ganapathi, Mythily | Gelb, Bruce D. | Jobanputra, Vaidehi | Wilson, Ashley | Greally, John | Jacquemont, Sebastien | Jizi, Khadije | Bruel, Ange-Line | Quelin, Chloe | Misra, Vinod K. | Chick, Erika | Romano, Corrado | Greco, Donatella | Arena, Alessia | Morleo, Manuela | Nigro, Vincenzo | Seyama, Rie | Uchiyama, Yuri | Matsumoto, Naomichi | Taira, Ryoji | Tashiro, Katsuya | Sakai, Yasunari | Yigit, Gokhan | Wollnik, Bernd | Wagner, Michael | Kutsche, Barbara | Hurst, Anna C. E. | Thompson, Michelle L. | Schmidt, Ryan | Randolph, Linda | Spillmann, Rebecca C. | Shashi, Vandana | Higginbotham, Edward J. | Cordeiro, Dawn | Carnevale, Amanda | Costain, Gregory | Khan, Tayyaba | Funalot, Benoit | Mau-Them, Frederic Tran | Moya, Luis Fernandez Garcia | Garcia-Minaur, Sixto | Osmond, Matthew | Chad, Lauren | Quercia, Nada | Carrasco, Diana | Li, Chumei | Sanchez-Valle, Amarilis | Kelley, Meghan | Nizon, Mathilde | Jensson, Brynjar O. | Sulem, Patrick | Stefansson, Kari | Gorokhova, Svetlana | Busa, Tiffany | Rio, Marlene | Habdallah, Hamza Hadj | Lesieur-Sebellin, Marion | Amiel, Jeanne | Pingault, Veronique | Mercier, Sandra | Vincent, Marie | Philippe, Christophe | Fatus-Fauconnier, Clemence | Friend, Kathryn | Halligan, Rebecca K. | Biswas, Sunita | Rosser, Jane | Shoubridge, Cheryl | Corbett, Mark | Barnett, Christopher | Gecz, Jozef | Leppig, Kathleen | Slavotinek, Anne | Marcelis, Carlo | Pfundt, Rolph | Vries, Bert B. A., De | Slegtenhorst, Marjon A., Van | Brooks, Alice S. | Cogne, Benjamin | Rambaud, Thomas | Tumer, Zeynep | Zackai, Elaine H. | Akizu, Naiara | Song, Yuanquan | Hakonarson, Hakon
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CCSD ; American Society for Clinical Investigation -
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Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, ourunderstanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants inU2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelatedindividuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals withde novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced inhuman neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural lossof function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning,and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profilingrevealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients withNDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors asNDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function
