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https://ahro.austin.org.au/austinjspui/handle/1/16250| Title: | De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome | Austin Authors: | Kim, Jung-Hyun;Shinde, Deepali N;Reijnders, Margot RF;Hauser, Natalie S;Belmonte, Rebecca L;Wilson, Gregory R;Bosch, Daniëlle GM;Bubulya, Paula A;Shashi, Vandana;Petrovski, Slavé;Stone, Joshua K;Park, Eun Young;Veltman, Joris A;Sinnema, Margje;Stumpel, Connie TRM;Draaisma, Jos M;Nicolai, Joost;Yntema, Helger G;Lindstrom, Kristin;de Vries, Bert B AA;Jewett, Tamison;Santoro, Stephanie L;Vogt, Julie;Bachman, Kristine K;Seeley, Andrea H;Krokosky, Alyson;Turner, Clesson;Rohena, Luis;Hempel, Maja;Kortüm, Fanny;Lessel, Davor;Neu, Axel;Strom, Tim M;Wieczorek, Dagmar;Bramswig, Nuria;Laccone, Franco A;Behunova, Jana;Rehder, Helga;Gordon, Christopher T;Rio, Marlène;Romana, Serge;Tang, Sha;El-Khechen, Dima;Cho, Megan T;McWalter, Kirsty;Douglas, Ganka;Baskin, Berivan;Begtrup, Amber;Funari, Tara;Schoch, Kelly;Stegmann, Alexander PA;Stevens, Servi JC;Zhang, Dong-Er;Traver, David;Yao, Xu;MacArthur, Daniel G;Brunner, Han G;Mancini, Grazia M;Myers, Richard M;Owen, Laurie B;Lim, Ssang-Taek;Stachura, David L;Vissers, Lisenka ELM;Ahn, Eun-Young Erin | Institutional Author: | University of Washington Center for Mendelian Genomics Deciphering Developmental Disorders Study |
Affiliation: | Austin Health, Heidelberg, Victoria, Australia Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA Ambry Genetics, Aliso Viejo, CA, USA Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, USA Department of Biological Sciences, California State University, Chico, CA, USA Department of Biological Sciences, Wright State University, Dayton, OH, USA Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, the University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia Institute for Genomic Medicine, Columbia University, New York, NY, USA Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands Department of Pediatrics, Radboudumc Amalia Children’s Hospital, Nijmegen, the Netherlands Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ, USA Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA Nationwide Children’s Hospital, Columbus, OH, USA Ohio State University College of Medicine, Columbus, OH, USA West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham, UK Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK Geisinger Medical Center, Danville, PA, USA Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, USA Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX, USA Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, T, USA Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Human Genetics, Technical University of Munich, Munich, Germany Institute of Human Genetics, University Clinic Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, Essen, Germany Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France Service de Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD, USA Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA Department of Pathology, University of California, San Diego, La Jolla, CA, USA Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA Broad Institute of MIT and Harvard, Cambridge, MA, USA Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA |
Issue Date: | 1-Sep-2016 | Date: | 2016-09-01 | Publication information: | American Journal of Human Genetics 2016; 99(3): 711-719 | Abstract: | 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. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/16250 | DOI: | 10.1016/j.ajhg.2016.06.029 | Journal: | American Journal of Human Genetics | PubMed URL: | https://pubmed.ncbi.nlm.nih.gov/27545680 | Type: | Journal Article |
| Appears in Collections: | Journal articles |
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