Please use this identifier to cite or link to this item: 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
metadata.dc.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: http://ahro.austin.org.au/austinjspui/handle/1/16250
DOI: 10.1016/j.ajhg.2016.06.029
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/27545680
Type: Journal Article
Appears in Collections:Journal articles

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