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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

  1. Author:
    Li, Dong
    Wang, Qin
    Bayat, Allan
    Battig, Mark R
    Zhou, Yijing
    Bosch, Daniëlle Gm
    van Haaften, Gijs
    Granger, Leslie
    Petersen, Andrea K
    Pérez-Jurado, Luis A
    Aznar-Laín, Gemma
    Aneja, Anushree
    Hancarova, Miroslava
    Bendova, Sarka
    Schwarz, Martin
    Kremlíková Pourová, Radka
    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 C
    Li, Megan
    Tarnopolsky, Mark
    Brady, Lauren
    Parker, Michael J
    Faghfoury, Hanna
    Parsley, Lea Kristin
    Agolini, Emanuele
    Dentici, Maria Lisa
    Novelli, Antonio
    Wright, Meredith S
    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 J
    Lyons, Michael J
    Douglas, Jessica
    Nowak, Catherine B
    Afenjar, Alexandra
    Hoyer, Juliane
    Keren, Boris
    Maas, Saskia M
    Motazacker, Mahdi M
    Martinez-Agosto, Julian A
    Rabani, Ahna M
    McCormick, Elizabeth M
    Falk, Marni
    Ruggiero, Sarah M
    Helbig, Ingo
    Møller, Rikke S
    Tessarollo,Lino
    Tomassoni Ardori,Francesco
    Palko,Mary Ellen
    Hsieh, Tzung-Chien
    Krawitz, Peter M
    Ganapathi, Mythily
    Gelb, Bruce D
    Jobanputra, Vaidehi
    Wilson, Ashley
    Greally, John
    Jacquemont, Sébastien
    Jizi, Khadijé
    Ange-Line, Bruel
    Quelin, Chloé
    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, Gökhan
    Wollnik, Bernd
    Wagner, Michael
    Kutsche, Barbara
    Hurst, Anna Ce
    Thompson, Michelle L
    Schmidt, Ryan J
    Randolph, Linda M
    Spillmann, Rebecca C
    Shashi, Vandana
    Higginbotham, Edward J
    Cordeiro, Dawn
    Carnevale, Amanda
    Costain, Gregory
    Khan, Tayyaba
    Funalot, Benoît
    Tran Mau-Them, Frederic
    Fernandez Garcia Moya, Luis
    García-Miñaúr, 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, Marlène
    Hadj Abdallah, Hamza
    Lesieur-Sebellin, Marion
    Amiel, Jeanne
    Pingault, Véronique
    Mercier, Sandra
    Vincent, Marie
    Philippe, Christophe
    Fatus-Fauconnier, Clemence
    Friend, Kathryn
    Halligan, Rebecca K
    Biswas, Sunita
    Rosser, Jane Mr
    Shoubridge, Cheryl
    Corbett, Mark A
    Barnett, Christopher
    Gecz, Jozef
    Leppig, Kathleen A
    Slavotinek, Anne
    Marcelis, Carlo
    Pfundt, Rolph
    de Vries, Bert Ba
    van Slegtenhorst, Marjon A
    Brooks, Alice S
    Cogne, Benjamin
    Rambaud, Thomas
    Tümer, Zeynep
    Zackai, Elaine H
    Akizu, Naiara
    Song, Yuanquan
    Hakonarson, Hakon

  2. Author Address

    Center for Applied Genomics, Children 39;s Hospital of Philadelphia, Philadelphia, United States of America., Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children 39;s Hospital of Philadelphia, Philadelphia, United States of America., Department of Regional Health Research, University of Southern Denmark, Dianalund, Denmark., Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands., Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Department of Genetics and Metabolism, Randall Children 39;s Hospital at Legacy Emanuel Medical Center, Portland, United States of America., Universitat Pompeu Fabra, Barcelona, Spain., Pediatric Neurology, Hospital del Mar Research Institute, Barcelona, Spain., Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic., Division of Human Genetics, Children 39;s Hospital of Philadelphia, Philadelphia, United States of America., Children 39;s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada., Ambry Genetics, Aliso Viejo, United States of America., Invitae, San Francisco, United States of America., Division of Neuromuscular and Neurometabolic Disorders, Department of Paedi, McMaster University Children 39;s Hospital, Hamilton, Canada., Sheffield Clinical Genetics Service, Sheffield Children 39;s Hospital, Sheffield, United Kingdom., The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Canada., University of Illinois College of Medicine, Mercy Health Systems, Rockford, United States of America., Laboratory of Medical Genetics, Translational Cytogenomics Research Unit,, Bambino Ges 249; Children 39;s Hospital, IRCCS, Rome, Italy., Medical Genetics Unit, Academic Department of Pediatrics, IRCCS Ospedale Pediatrico Bambino Ges 249;, Rome, Italy., Clinical Genomics Center, Rady Children 39;s Institute for Genomic Medicine, San Diego, United States of America., Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States of America., Division of Pediatric Pulmonary and Sleep Medicine, University of Utah, Salt Lake City, United States of America., Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Mater, University of Genoa, Genoa, Italy., Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Mater, University of Genova, Genova, Italy., Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Department of Genetics, Southern California Permanente Medical Group, Kaiser Permanente, San Diego, United States of America., Department of Genetics, Kaiser Permanente, Los Angeles, United States of America., Center for Development, Behavior and Genetics, SUNY Upstate Medical University, Syracuse, United States of America., Division of Genetics, Department of Pediatrics, London Health Sciences Centre, London, Canada., Genetics, Greenwood Genetic Center, Greenwood, United States of America., Division of Genetics and Genomics, Boston Children 39;s Hospital, Boston, United States of America., Division of Genetics and Metabolism, MassGeneral Hospital for Children, Boston, United States of America., Genetics Service, Reference Center for Intellectual Disabilities of Rare Ca, Hospital Trousseau, Paris, France., Institute of Human Genetics, Friedrich-Alexander-Universit 228;t Erlangen-N 252;rnberg, Erlangen, Germany., Department of Genetics, University Hospitals Piti 233; Salp 234;tri 232;re - Charles Foix, Paris, France., Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Laboratory of Genome Diagnostics, Department of Human Genetics, University of Amsterdam, Amsterdam, Netherlands., Division of Medical Genetics, Department of Pediatrics, UCLA, Los Angeles, United States of America., Mitochondrial Medicine Frontier Program, Division of Human Genetics, Depart, Children 39;s Hospital of Philadelphia, Philadelphia, United States of America., Division of Neurology, Children 39;s Hospital of Philadelphia, Philadelphia, United States of America., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, United States of America., Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany., Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America., Mindich Child Health and Development Institute and the Departments of Pedia, Icahn School of Medicine at Mount Sinai, New York, United States of America., CLIA, New York Genome Center, New York, United States of America., Department of Genetics, Albert Einstein College of Medicine, Bronx, United States of America., Division of Genetics and Genomics, CHU Ste-Justine Hospital, Montreal, Canada., GAD - University Burgundy Franche-Comt 233;, UMR1231 Inserm, Dijon, France., Medical Genetics Department, CLAD-Ouest Rare Disease Reference Center, University Hospital South, Rennes, France., Division of Genetic, Genomic, and Metabolic Disorders, Children 39;s Hospital of Michigan, Detroit, United States of America., Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Telethon Institute of Genetics and Medicine, Naples, Italy., Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Department of Pediatrics, Kyushu University, Fukuoka, United States of America., Department of Pediatrics, Karatsu Red Cross Hospital, Saga, Japan., Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany., Kinderzentrum Oldenburg, Diakonisches Werk Oldenburg, Oldenburg, Germany., Department of Genetics, University of Alabama at Birmingham, Birmingham, United States of America., HudsonAlpha Institute for Biotechnology, Huntsville, United States of America., Department of Pathology and Laboratory Medicine, Children 39;s Hospital Los Angeles, Los Angeles, United States of America., Division of Medical Genetics, Children 39;s Hospital Los Angeles, Los Angeles, United States of America., Department of Pediatrics-Medical Genetics, Duke University School of Medicine, Durham, United States of America., Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada., Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada., INSERM U.573, Paris, France., Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid, Spain., Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada., Department of Genetic Counselling, The Hospital for Sick Children, Ottawa, Canada., Department of Clinical Genetics, Cook Children 39;s Hospital, Fort Worth, United States of America., Division of Genetics, Department of Pediatrics, McMaster University, Hamilton, Canada., Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, United States of America., Medical Genetics Service, Nantes University Hospital, Nantes, France., deCODE genetics, Amgen Inc., Reykjavik, Iceland., Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Department of Medical Genetics, Timone Hospital, Marseille, France., Department of Genomic Medicine of Rare Disorders, Necker Hospital, PARIS, France., Rare Disease Genetics Department, Necker Hospital, Paris, France., Competence Center for Hereditary Metabolic Diseases, University Hospital Dijon Burgundy, Dijon, France., Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia., Metabolic Clinic, Women 39;s and Children 39;s Hospital, Adelaide, Australia., Department of General Medicine, Women 39;s and Children 39;s Hospital, Adelaide, Australia., Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, Australia., Genetic Services, Kaiser Permenante of Washington, Seattle, United States of America., Department of Pediatrics, Cincinnati Children 39;s Hospital Medical Center, Cincinnati, United States of America., Department of Human Genetics, Donders Institute for Brain, Cognition and Be, Radboud University Medical Center, Nijmegen, Netherlands., SeqOIA Multi-Site Medical Biology Laboratory, Paris, France., Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup - Copenhagen, Denmark., Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America.,
    1. Year: 2024
    2. Date: Jan 2
    3. Epub Date: 2023 11 14
  2. Journal: The Journal of clinical investigation
    1. 134
    2. 1
    3. Pages: e171235
  4. Type of Article: Article
  5. Article Number: e171235
  1. Abstract:

    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.

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  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1172/JCI171235
  3. PMID: 37962958
  4. PMCID: PMC10760965
  5. View record in Web of Science®
  6. WOS: 001171162100005
  7. PII : 171235

Library Notes

  1. Fiscal Year: FY2023-2024
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