Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Pourova RK, Sedlacek Z, Keena BA, March ME, Hou C, O’Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Ardori FT, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Mau-Them FT, Garcia Moya LF, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Habdallah HH, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, Hakonarson H (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 134

Article Number: e171235

Journal Issue: 1

DOI: 10.1172/JCI171235

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 7 recurrent variants in 30 individuals) and 6 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 (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 profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Authors with CRIS profile

Involved external institutions

SUNY Upstate Medical University United States (USA) (US) Motol University Hospital / Fakultní nemocnice v Motole Czech Republic (CZ) Children's Hospital of Philadelphia United States (USA) (US) University of Southern Denmark / Syddansk Universitet Denmark (DK) Erasmus University Medical Center (MC) Netherlands (NL) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Randall Children's Hospital at Legacy Emanuel United States (USA) (US) Ciber de Enfermedades Raras (CIBERER) Spain (ES) Universitat Pompeu Fabra (UPF) Spain (ES) University of California Los Angeles (UCLA) United States (USA) (US) Universitätsklinikum Göttingen Germany (DE) The Hospital for Sick Children (SickKids) Canada (CA) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario Canada (CA) Rady Children's Hospital San Diego United States (USA) (US) Ambry Genetics United States (USA) (US) Invitae Corporation United States (USA) (US) London Health Sciences Centre Canada (CA) McMaster University Canada (CA) Sheffield Children's NHS Foundation Trust United Kingdom (GB) Donders Institute for Brain, Cognition and Behaviour Netherlands (NL) Hôpital Necker-Enfants malades France (FR) Université de Nantes France (FR) GCS SeqOIA France (FR) Rigshospitalet Denmark (DK) IRCCS Associazione Oasi Maria Santissima Italy (IT) Ospedale Pediatrico Bambino Gesu Italy (IT) Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) University of Utah United States (USA) (US) Yokohama City University Japan (JP) Boston Children's Hospital United States (USA) (US) University of Toronto Canada (CA) University of Genova / Università degli Studi di Genova Italy (IT) Greenwood Genetic Center United States (USA) (US) Istituto Giannina Gaslini Italy (IT) Kaiser Permanente United States (USA) (US) Massachusetts General Hospital United States (USA) (US) Hôpital Armand-Trousseau (AP-HP) France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) University of Amsterdam Netherlands (NL) Children's Hospital Los Angeles United States (USA) (US) Cardiovascular Research Foundation United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Keck School of Medicine of USC United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) Duke University United States (USA) (US) Albert Einstein College of Medicine United States (USA) (US) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Cook Children's Medical Center United States (USA) (US) Université de Bourgogne (uB) / University of Burgundy / University of Dijon France (FR) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) University of Illinois at Chicago United States (USA) (US) Children's Hospital of Michigan United States (USA) (US) SA Pathology Australia (AU) Perelman School of Medicine University of Pennsylvania United States (USA) (US) Karatsu Red Cross Hospital / 唐津赤十字病院 Japan (JP) Morsani College of Medicine United States (USA) (US) The Frederick National Laboratory for Cancer Research United States (USA) (US) Kinderzentrum Oldenburg (Sozialpädiatrisches Zentrum) Germany (DE) deCODE genetics Iceland (IS) Cardiology PC United Kingdom (GB) Aix-Marseille University / Aix-Marseille Université France (FR) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) HudsonAlpha United States (USA) (US) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) Hospital Universitario La Paz Spain (ES) Women’s and Children’s Hospital Australia (AU) Hôpital de la Timone France (FR) University of Adelaide Australia (AU) Université Sorbonne Paris Cité France (FR) Cincinnati Children's Hospital Medical Center United States (USA) (US)

How to cite

APA:

Li, D., Wang, Q., Bayat, A., Battig, M.R., Zhou, Y., Bosch, D.G.,... Hakonarson, H. (2024). Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. Journal of Clinical Investigation, 134(1). https://dx.doi.org/10.1172/JCI171235

MLA:

Li, Dong, et al. "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features." Journal of Clinical Investigation 134.1 (2024).

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