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Am J Hum Genet. 2016 Sep 1;99(3):711-9. doi: 10.1016/j.ajhg.2016.06.029. Epub 2016 Aug 18.

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Author information

  • 1Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
  • 2Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 3Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 4Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
  • 5Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
  • 6Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
  • 7Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • 8Department of Medicine, University of Melbourne, Austin Hospital and Royal Melbourne Hospital, Parkville, VIC 3010, Australia; Institute for Genomic Medicine, Columbia University, New York, NY 10027, USA.
  • 9Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 10Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 11Department of Pediatrics, Radboudumc Amalia Children's Hospital, 6500 HB Nijmegen, the Netherlands.
  • 12Department of Neurology, Maastricht University Medical Center, 6299 HX Maastricht, the Netherlands.
  • 13Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 14Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • 15Nationwide Children's Hospital, Columbus, OH 43205, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA.
  • 16West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
  • 17Geisinger Medical Center, Danville, PA 17822, USA.
  • 18Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA.
  • 19Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 20Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 21Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 22Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
  • 23Institute of Human Genetics, University Clinic Düsseldorf, Heinrich-Heine-University, 40225 Düsseldorf, Germany; Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
  • 24Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
  • 25Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria.
  • 26Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
  • 27Département de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 28Service de Cytogénétique, Hôpital Necker-Enfants Malades, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
  • 29GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 30Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 31Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 32Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • 33Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 34Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
  • 35HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 36Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
  • 37Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: lisenka.vissers@radboudumc.nl.
  • 38Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA. Electronic address: eahn@health.southalabama.edu.

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.

PMID:
27545680
PMCID:
PMC5011044
[Available on 2017-03-01]
DOI:
10.1016/j.ajhg.2016.06.029
[PubMed - in process]
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