Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Dong Li; Qin Wang; Allan Bayat; Mark R. Battig; Yijing Zhou; Danielle G. M. Bosch; Gijs van Haaften; Leslie Granger; Andrea K. Petersen; Luis A. Perez-Jurado; Gemma Aznar-Lain; Anushree Aneja; Miroslava Hancarova; Sarka Bendova; Martin Schwarz; Radka Kremlikova Pourova; 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 Towne; Megan Li; Mark Tarnopolsky; Lauren Brady; Michael J. Parker; Hanna Faghfoury; Lea Kristin Parsley; Emanuele Agolini; Maria Lisa Dentici; Antonio Novelli; Meredith 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 Louie; Michael Lyons; Jessica Douglas; Catherine Nowak; Alexandra Afenjar; Juliane Hoyer; Boris Keren; Saskia M. Maas; Mahdi M. Motazacker; Julian A. Martinez-Agosto; Ahna M. Rabani; Elizabeth M. McCormick; Marni J. Falk; Sarah M. Ruggiero; Ingo Helbig; Rikke S. Moller; 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; Sebastien Jacquemont; Khadije Jizi; Ange-Line Bruel; Chloe 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; Gokhan Yigit; Bernd Wollnik; Michael Wagner; Barbara Kutsche; Anna C. E. Hurst; Michelle L. Thompson; Ryan Schmidt; Linda Randolph; Rebecca C. Spillmann; Vandana Shashi; Edward J. Higginbotham; Dawn Cordeiro; Amanda Carnevale; Gregory Costain; Tayyaba Khan; Benoit Funalot; Frederic Tran Mau-Them; Luis Fernandez Garcia Moya; Sixto Garcia-Minaur; 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; Marlene Rio; Hamza Hadj Habdallah; Marion Lesieur-Sebellin; Jeanne Amiel; Veronique Pingault; Sandra Mercier; Marie Vincent; Christophe Philippe; Clemence Fatus-Fauconnier; Kathryn Friend; Rebecca K. Halligan; Sunita Biswas; Jane Rosser; Cheryl Shoubridge; Mark Corbett; Christopher Barnett; Jozef Gecz; Kathleen Leppig; Anne Slavotinek; Carlo Marcelis; Rolph Pfundt; Bert B. A. de Vries; Marjon A. van Slegtenhorst; Alice S. Brooks; Benjamin Cogne; Thomas Rambaud; Zeynep Tumer; Elaine H. Zackai; Naiara Akizu; Yuanquan Song; Hakon Hakonarson

doi:10.1172/JCI171235

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Article de revue

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Dong Li, Qin Wang, Allan Bayat, Mark R. Battig, Yijing Zhou, Danielle G. M. Bosch, Gijs van Haaften, Leslie Granger, Andrea K. Petersen, Luis A. Perez-Jurado, …

The Journal of clinical investigation, Vol.134(1), pp.1-16

01/01/2024

DOI: https://doi.org/10.1172/JCI171235

PMID: 37962958

Résumé

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Science & Technology

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.

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Titre: Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
Créateurs - sans rôle: Dong Li - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Qin Wang - Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
Allan Bayat - Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark
Mark R. Battig - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Yijing Zhou - Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
Danielle G. M. Bosch - Erasmus MC
Gijs van Haaften - Univ Utrecht, Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, Utrecht, Netherlands
Leslie Granger - Randall Childrens Hosp, Legacy Emanuel Med Ctr, Dept Genet & Metab, Portland, OR USA
Andrea K. Petersen - College Station Medical Center
Luis A. Perez-Jurado - ISCIII, Ctr Invest Biomed Red Enfamedades Raras, Madrid, Spain
Gemma Aznar-Lain - Univ Pompeu Fabra, Barcelona, Spain
Anushree Aneja - Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
Miroslava Hancarova - Charles University
Sarka Bendova - Charles University
Martin Schwarz - Charles Univ Prague, Fac Med 2, Dept Biol & Med Genet, Prague, Czech Republic
Radka Kremlikova Pourova - Charles Univ Prague, Fac Med 2, Dept Biol & Med Genet, Prague, Czech Republic
Zdenek Sedlacek - Charles Univ Prague, Fac Med 2, Dept Biol & Med Genet, Prague, Czech Republic
Beth A. Keena - Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA
Michael E. March - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Cuiping Hou - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Nora O'Connor - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Elizabeth J. Bhoj - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Margaret H. Harr - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Gabrielle Lemire - Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, Ottawa, ON, Canada
Kym M. Boycott - University of Ottawa
Meghan Towne - Ambry Genet, Aliso Viejo, CA USA
Megan Li - Invitae, San Francisco, CA USA
Mark Tarnopolsky - McMaster Univ, Dept Paediat, Div Neuromuscular & Neurometab Disorders, Childrens Hosp, Hamilton, ON, Canada
Lauren Brady - McMaster Univ, Dept Paediat, Div Neuromuscular & Neurometab Disorders, Childrens Hosp, Hamilton, ON, Canada
Michael J. Parker - Sheffield Childrens Hosp, Dept Clin Genet, Sheffield, S Yorkshire, England
Hanna Faghfoury - Univ Hlth Network, Toronto, ON, Canada
Lea Kristin Parsley - Univ Illinois, Mercy Hlth Syst, Coll Med, Rockford, IL USA
Emanuele Agolini - Bambino Gesu Pediat Hosp, Translat Cytogen Res Unit, Lab Med Genet, IRCCS, Rome, Italy
Maria Lisa Dentici - Osped Pediat Bambino Gesu, Med Genet Unit, Acad Dept Pediat, IRCCS, Rome, Italy
Antonio Novelli - Bambino Gesu Pediat Hosp, Translat Cytogen Res Unit, Lab Med Genet, IRCCS, Rome, Italy
Meredith Wright - Rady Childrens Inst Genom Med, San Diego, CA USA
Rachel Palmquist - Univ Utah, Sch Med, Dept Pediat, Div Pediat Neurol, Salt Lake City, UT USA
Khanh Lai - Univ Utah, Div Pediat Pulm & Sleep Med, Salt Lake City, UT USA
Marcello Scala - University of Genoa
Pasquale Striano - University of Genoa
Michele Iacomino - Ist Giannina Gaslini, Med Genet Unit, IRCCS, Genoa, Italy
Federico Zara - Ist Giannina Gaslini, Med Genet Unit, IRCCS, Genoa, Italy
Annina Cooper - Kaiser Permanente, Dept Genet, Southern Calif Permanente Med Grp, San Diego, CA USA
Timothy J. Maarup - Kaiser Permanente, Dept Genet, Los Angeles, CA USA
Melissa Byler - SUNY Upstate Med Univ, Ctr Dev Behav & Genet, Syracuse, NY 13210 USA
Robert Roger Lebel - SUNY Upstate Med Univ, Ctr Dev Behav & Genet, Syracuse, NY 13210 USA
Tugce B. Balci - London Hlth Sci Ctr, Dept Paediat, Div Genet, London, ON, Canada
Raymond Louie - Greenwood Genet Ctr, Greenwood, SC 29646 USA
Michael Lyons - Greenwood Genet Ctr, Greenwood, SC 29646 USA
Jessica Douglas - Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA
Catherine Nowak - Mass Gen Hosp Children, Div Genet & Metab, Boston, MA USA
Alexandra Afenjar - Assistance Publique – Hôpitaux de Paris
Juliane Hoyer - Friedrich-Alexander-Universität Erlangen-Nürnberg
Boris Keren - Hosp Pitre Salpetriere, Dept Genet, Paris, France
Saskia M. Maas - University of Amsterdam
Mahdi M. Motazacker - Univ Amsterdam, Dept Human Genet, Lab Genome Diagnost, Amsterdam UMC, Amsterdam, Netherlands
Julian A. Martinez-Agosto - College Station Medical Center
Ahna M. Rabani - UCLA, Div Med Genet, Dept Pediat, Los Angeles, CA USA
Elizabeth M. McCormick - Childrens Hosp Philadelphia, Div Human Genet, Mitochondrial Med Frontier Program, Dept Pediat, Philadelphia, PA USA
Marni J. Falk - Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA
Sarah M. Ruggiero - Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA
Ingo Helbig - Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA
Rikke S. Moller - Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark
Lino Tessarollo - NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD USA
Francesco Tomassoni Ardori - NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD USA
Mary Ellen Palko - NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD USA
Tzung-Chien Hsieh - Rheinische Friedrich Wilhelms Univ Bonn, Inst Genom Stat & Bioinformat, Univ Hosp Bonn, Bonn, Germany
Peter M. Krawitz - Rheinische Friedrich Wilhelms Univ Bonn, Inst Genom Stat & Bioinformat, Univ Hosp Bonn, Bonn, Germany
Mythily Ganapathi - New York Genome Ctr, New York, NY USA
Bruce D. Gelb - Icahn Sch Med, Mindich Child Hlth & Dev Inst, New York, NY USA
Vaidehi Jobanputra - New York Genome Ctr, New York, NY USA
Ashley Wilson - New York Genome Ctr, New York, NY USA
John Greally - Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA
Sebastien Jacquemont - Univ Montreal, Div Genet & Genom, CHU Ste Justine Hosp, Montreal, PQ, Canada
Khadije Jizi - Univ Montreal, Div Genet & Genom, CHU Ste Justine Hosp, Montreal, PQ, Canada
Ange-Line Bruel - Univ Bourgogne Franche Comte, Genet Dev Anomalies, INSERM UMR 1231, Dijon, France
Chloe Quelin - CHU Hop Sud, Med Genet Dept, Ctr Reference Malad Rares CLAD Ouest, Rennes, France
Vinod K. Misra - Childrens Hosp Michigan, Div Genet Genom & Metab Disorders, Detroit, MI 48201 USA
Erika Chick - Childrens Hosp Michigan, Div Genet Genom & Metab Disorders, Detroit, MI 48201 USA
Corrado Romano - Oasi Res Inst IRCCS, Res Unit Rare Dis & Neurodev Disorders, Troina, Italy
Donatella Greco - Oasi Res Inst IRCCS, Troina, Italy
Alessia Arena - Oasi Res Inst IRCCS, Troina, Italy
Manuela Morleo - Telethon Inst Genet & Med TIGEM, Naples, Italy
Vincenzo Nigro - College Station Medical Center
Rie Seyama - Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa, Japan
Yuri Uchiyama - Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa, Japan
Naomichi Matsumoto - Yokohama City University
Ryoji Taira - Kyushu Univ, Grad Sch Med Sci, Dept Pediat, Fukuoka, Japan
Katsuya Tashiro - Karatsu Red Cross Hosp, Dept Pediat, Saga, Japan
Yasunari Sakai - Kyushu Univ, Grad Sch Med Sci, Dept Pediat, Fukuoka, Japan
Gokhan Yigit - Univ Med Ctr Gottingen, Inst Human Genet, Gottingen, Germany
Bernd Wollnik - Univ Med Ctr Gottingen, Inst Human Genet, Gottingen, Germany
Michael Wagner - Diakon Werk Oldenburg, Sozialpadiatr Zentrum, Kinderzentrum Oldenburg, Oldenburg, Germany
Barbara Kutsche - Diakon Werk Oldenburg, Sozialpadiatr Zentrum, Kinderzentrum Oldenburg, Oldenburg, Germany
Anna C. E. Hurst - Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA
Michelle L. Thompson - HudsonAlpha Inst Biotechnol, Huntsville, AL USA
Ryan Schmidt - Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA
Linda Randolph - Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA
Rebecca C. Spillmann - Duke Univ, Dept Pediat Med Genet, Sch Med, Durham, NC USA
Vandana Shashi - Duke University
Edward J. Higginbotham - Hosp Sick Children, Genome Diagnost, Dept Paediat Lab Med, Toronto, ON, Canada
Dawn Cordeiro - Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
Amanda Carnevale - Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
Gregory Costain - Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
Tayyaba Khan - Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
Benoit Funalot - Hop Henri Mondor, AP HP, Dept Genet, Creteil, France
Frederic Tran Mau-Them - Inserm
Luis Fernandez Garcia Moya - Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, Madrid, Spain
Sixto Garcia-Minaur - Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, Madrid, Spain
Matthew Osmond - University of Ottawa
Lauren Chad - Univ Toronto, Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, ON, Canada
Nada Quercia - Hosp Sick Children, Dept Genet Counselling, Div Clin & Metab Genet, Ottawa, ON, Canada
Diana Carrasco - Cook Childrens Hosp, Dept Clin Genet, Ft Worth, TX USA
Chumei Li - McMaster Univ, Dept Paediat, Div Genet, Hamilton, ON, Canada
Amarilis Sanchez-Valle - Univ S Florida, Dept Pediat, Div Genet & Metab, Tampa, FL USA
Meghan Kelley - Univ S Florida, Dept Pediat, Div Genet & Metab, Tampa, FL USA
Mathilde Nizon - Université de Nantes
Brynjar O. Jensson - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Patrick Sulem - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Kari Stefansson - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Svetlana Gorokhova - Inserm
Tiffany Busa - Assistance Publique Hôpitaux de Marseille
Marlene Rio - Univ Paris Cite, Necker Hosp, AP HP Ctr, Dept Genom Med Rare Disorders, Paris, France
Hamza Hadj Habdallah - Univ Paris Cite, Necker Hosp, AP HP Ctr, Dept Genom Med Rare Disorders, Paris, France
Marion Lesieur-Sebellin - Univ Paris Cite, Necker Hosp, AP HP Ctr, Dept Genom Med Rare Disorders, Paris, France
Jeanne Amiel - Assistance Publique – Hôpitaux de Paris
Veronique Pingault - Assistance Publique – Hôpitaux de Paris
Sandra Mercier - Université de Nantes
Marie Vincent - Université de Nantes
Christophe Philippe - Univ Bourgogne Franche Comte, Genet Dev Anomalies, INSERM UMR 1231, Dijon, France
Clemence Fatus-Fauconnier - CHU Dijon Bourgogne, Reference Ctr Hereditary Metab Dis, Dijon, France
Kathryn Friend - SA Pathol, Genet & Mol Pathol, Adelaide, SA, Australia
Rebecca K. Halligan - Womens & Childrens Hosp, Metab Clin, Adelaide, SA, Australia
Sunita Biswas - Womens & Childrens Hosp, Metab Clin, Adelaide, SA, Australia
Jane Rosser - Womens & Childrens Hosp, Dept Gen Med, Adelaide, SA, Australia
Cheryl Shoubridge - The University of Adelaide
Mark Corbett - Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia
Christopher Barnett - Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia
Jozef Gecz - The University of Adelaide
Kathleen Leppig - Kaiser Permenante Washington, Genet Serv, Washington, DC USA
Anne Slavotinek - College Station Medical Center
Carlo Marcelis - Radboud University Nijmegen
Rolph Pfundt - Radboud University Nijmegen
Bert B. A. de Vries - Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain, Dept Human Genet, Nijmegen, Netherlands
Marjon A. van Slegtenhorst - Erasmus MC
Alice S. Brooks - Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands
Benjamin Cogne - Université de Nantes
Thomas Rambaud - Lab Biol Med Multisites SeqOIA Lab Seqoiafr, Paris, France
Zeynep Tumer - Copenhagen Univ Hosp, Rigshosp, Kennedy Ctr, Dept Clin Genet, Glostrup, Denmark
Elaine H. Zackai - Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA
Naiara Akizu - Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
Yuanquan Song - Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
Hakon Hakonarson - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Détails de publication: The Journal of clinical investigation, Vol.134(1), pp.1-16
Éditeur: Amer Soc Clinical Investigation Inc
Nombre de pages: 16
Note de subvention: U01HG007672 / NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Office of the Director CHOP Roberts Collaborative Functional Genomics Rapid grant HG009610; R01NS107392 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Eagles Autism Foundation 4100088540 / Pennsylvania Department of Health Institutional Development Funds 23K07229; 23K07334 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) National Institute on Minority Health and Health Disparities (NIMHD); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Minority Health & Health Disparities (NIMHD) EXC 2067/1-390729940 / German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Germany's Excellence Strategy; German Research Foundation (DFG) Takeda Science Foundation; Takeda Science Foundation (TSF)
Identifiants: 99158806309311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article