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

Autor:	Kim JH; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Shinde DN; Ambry Genetics, Aliso Viejo, CA 92656, USA., Reijnders MRF; Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands., Hauser NS; Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA., Belmonte RL; Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA., Wilson GR; Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA., Bosch DGM; Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands., Bubulya PA; Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA., Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA., Petrovski S; Department 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., Stone JK; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Park EY; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Veltman JA; Department 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., Sinnema M; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Stumpel CTRM; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Draaisma JM; Department of Pediatrics, Radboudumc Amalia Children's Hospital, 6500 HB Nijmegen, the Netherlands., Nicolai J; Department of Neurology, Maastricht University Medical Center, 6299 HX Maastricht, the Netherlands., Yntema HG; Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands., Lindstrom K; Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA., de Vries BBA; Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands., Jewett T; Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Santoro SL; Nationwide Children's Hospital, Columbus, OH 43205, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA., Vogt J; West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK., Bachman KK; Geisinger Medical Center, Danville, PA 17822, USA., Seeley AH; Geisinger Medical Center, Danville, PA 17822, USA., Krokosky A; Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA., Turner C; Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA., Rohena L; Division 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., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Kortüm F; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Neu A; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Strom TM; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany., Wieczorek D; Institute 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., Bramswig N; Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany., Laccone FA; Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria., Behunova J; Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria., Rehder H; Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria., Gordon CT; Laboratory 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., Rio M; Département de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France., Romana S; Service de Cytogénétique, Hôpital Necker-Enfants Malades, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France., Tang S; Ambry Genetics, Aliso Viejo, CA 92656, USA., El-Khechen D; Ambry Genetics, Aliso Viejo, CA 92656, USA., Cho MT; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., McWalter K; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., Douglas G; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., Baskin B; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., Begtrup A; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., Funari T; GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA., Schoch K; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA., Stegmann APA; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Stevens SJC; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Zhang DE; Moores 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., Traver D; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA., Yao X; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA., MacArthur DG; Broad 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., Brunner HG; Department 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., Mancini GM; Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands., Myers RM; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA., Owen LB; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Lim ST; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA., Stachura DL; Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA., Vissers LELM; Department 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., Ahn EYE; Mitchell 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.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2016 Sep 01; Vol. 99 (3), pp. 711-719. Date of Electronic Publication: 2016 Aug 18.
DOI:	10.1016/j.ajhg.2016.06.029
Abstrakt:	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. (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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