2. Academic Validation
  3. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

  • Am J Hum Genet. 2019 Aug 1;105(2):403-412. doi: 10.1016/j.ajhg.2019.06.007.
Lot Snijders Blok 1,  Tjitske Kleefstra 2,  Hanka Venselaar 3,  Saskia Maas 4,  Hester Y Kroes 5,  Augusta M A Lachmeijer 5,  Koen L I van Gassen 5,  Helen V Firth 6,  Susan Tomkins 7,  Simon Bodek 7,  DDD Study 6,  Katrin Õunap 8,  Monica H Wojcik 9,  Christopher Cunniff 10,  Katherine Bergstrom 10,  Zoë Powis 11,  Sha Tang 11,  Deepali N Shinde 11,  Catherine Au 12,  Alejandro D Iglesias 12,  Kosuke Izumi 13,  Jacqueline Leonard 13,  Ahmad Abou Tayoun 14,  Samuel W Baker 14,  Marco Tartaglia 15,  Marcello Niceta 15,  Maria Lisa Dentici 15,  Nobuhiko Okamoto 16,  Noriko Miyake 17,  Naomichi Matsumoto 17,  Antonio Vitobello 18,  Laurence Faivre 19,  Christophe Philippe 18,  Christian Gilissen 20,  Laurens Wiel 21,  Rolph Pfundt 20,  Pelagia Deriziotis 22,  Han G Brunner 23,  Simon E Fisher 24
Affiliations

Affiliations

  • 1 Human Genetics Department, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands; Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500AH Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, PO Box 9104, 6500HE Nijmegen, the Netherlands. Electronic address: [email protected].
  • 2 Human Genetics Department, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, PO Box 9104, 6500HE Nijmegen, the Netherlands.
  • 3 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands.
  • 4 Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
  • 5 Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508AB Utrecht, the Netherlands.
  • 6 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 7 Clinical Genetics Service, University Hospitals Bristol National Health Service Foundation Trust, Bristol BS2 8HW, UK.
  • 8 Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu 51014, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu 51014, Estonia.
  • 9 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Newborn Medicine, Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 10 Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10021, USA.
  • 11 Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 12 Division of Clinical Genetics, Department of Pediatrics, New York Presbyterian Hospital, Columbia University, New York, NY 10032, USA.
  • 13 Division of Human Genetics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 14 Division of Genomic Diagnostics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 15 Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00146 Rome, Italy.
  • 16 Department of Medical Genetics, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
  • 17 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 18 UF Innovation en Diagnostic Génomique des Maladies Rares, Centre Hospitalier Universitaire Dijon Bourgogne, 21000 Dijon, France; INSERM UMR1231 Génétique des Anomalies du Développement, F-21000 Dijon, France.
  • 19 INSERM UMR1231 Génétique des Anomalies du Développement, F-21000 Dijon, France; Centre de Référence Maladies Rares « Anomalies du Développement et Syndrome Malformatifs » de l'Est, Centre de Génétique, Hôpital d'Enfants, Fédération Hospitalo-Universitaire Médecine TRANSLationnelle et Anomalies du Développement, Centre Hospitalier Universitaire Dijon Bourgogne, 21000 Dijon, France.
  • 20 Human Genetics Department, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands.
  • 21 Human Genetics Department, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands.
  • 22 Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500AH Nijmegen, the Netherlands.
  • 23 Human Genetics Department, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, PO Box 9104, 6500HE Nijmegen, the Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6202AZ Maastricht, the Netherlands.
  • 24 Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500AH Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, PO Box 9104, 6500HE Nijmegen, the Netherlands. Electronic address: [email protected].
PMID: 31303265 DOI: 10.1016/j.ajhg.2019.06.007
Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Keywords

BRET assay; Brain-1; FOXP2; POU3F2; POU3F3; de novo variants; intellectual disability; luciferase reporter; speech/language disorder.

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