한빛사 논문
Abstract
Jung-Hyun Kim1, 45, Deepali N. Shinde2, 45, Margot R.F. Reijnders3, 45, Natalie S. Hauser4, Rebecca L. Belmonte5, Gregory R. Wilson5, Daniëlle G.M. Bosch3, Paula A. Bubulya6, Vandana Shashi7, Slavé Petrovski8, 9, Joshua K. Stone1, Eun Young Park1, Joris A. Veltman3, 10, Margje Sinnema10, Connie T.R.M. Stumpel10, Jos M. Draaisma11, Joost Nicolai12, University of Washington Center for Mendelian Genomics Helger G. Yntema3, Kristin Lindstrom13, Bert B.A. de Vries3, Tamison Jewett14, Stephanie L. Santoro15, 16, Julie Vogt17, Deciphering Developmental Disorders Study18, Kristine K. Bachman19, Andrea H. Seeley19, Alyson Krokosky20, Clesson Turner20, Luis Rohena21, 22, Maja Hempel23, Fanny Kortüm23, Davor Lessel23, Axel Neu24, Tim M. Strom25, 26, Dagmar Wieczorek27, 28, Nuria Bramswig28, Franco A. Laccone29, Jana Behunova29, Helga Rehder29, Christopher T. Gordon30, 31, Marlène Rio32, Serge Romana33, 34, Sha Tang2, Dima El-Khechen2, Megan T. Cho35, Kirsty McWalter35, Ganka Douglas35, Berivan Baskin35, Amber Begtrup35, Tara Funari35, Kelly Schoch7, Alexander P.A. Stegmann10, Servi J.C. Stevens10, Dong-Er Zhang36, 37, 38, David Traver38, Xu Yao36, Daniel G. MacArthur39, 40, 41, Han G. Brunner3, 10, Grazia M. Mancini42, Richard M. Myers43, Laurie B. Owen1, Ssang-Taek Lim44, David L. Stachura5, Lisenka E.L.M. Vissers3, 45,*, Eun-Young Erin Ahn1, 44, 45,*
1 Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
2 Ambry Genetics, Aliso Viejo, CA 92656, USA
3 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
4 Medical Genetics and Metabolism, Valley Children’s Hospital, Madera, CA 93636, USA
5 Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA
6 Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA
7 Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA
8 Department of Medicine, University of Melbourne, Austin Hospital and Royal Melbourne Hospital, Parkville, VIC 3010, Australia
9 Institute for Genomic Medicine, Columbia University, New York, NY 10027, USA
10 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands
11 Department of Pediatrics, Radboudumc Amalia Children’s Hospital, 6500 HB Nijmegen, the Netherlands
12 Department of Neurology, Maastricht University Medical Center, 6299 HX Maastricht, the Netherlands
13 Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
14 Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
15 Nationwide Children’s Hospital, Columbus, OH 43205, USA
16 Ohio State University College of Medicine, Columbus, OH 43210, USA
17 West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham B15 2TG, UK
18 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
19 Geisinger Medical Center, Danville, PA 17822, USA
20 Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA
21 Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA
22 Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
23 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
24 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
25 Institute of Human Genetics, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany
26 Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany
27 Institute of Human Genetics, University Clinic Dusseldorf, Heinrich-Heine-University, 40225 Dusseldorf, Germany
28 Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany
29 Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria
30 Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France
31 Universite Paris Descartes, Sorbonne Paris Cite, Institut Imagine, 75015 Paris, France
32 Departement de Genetique, Hopital Necker-Enfants Malades, 75015 Paris, France
33 Service de Cytogenetique, Hopital Necker-Enfants Malades, 75015 Paris, France
34 Paris Descartes-Sorbonne Paris Cite University, Institut Imagine, 75015 Paris, France
35 GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA
36 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
37 Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
38 Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
39 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
40 Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
41 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
42 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands
43 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
44 Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
45 These authors contributed equally to this work
*Corresponding author
The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
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