2. Academic Validation
  3. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

  • Am J Hum Genet. 2017 Sep 7;101(3):428-440. doi: 10.1016/j.ajhg.2017.07.010.
Ekaterina L Ivanova 1,  Frédéric Tran Mau-Them 2,  Saima Riazuddin 3,  Kimia Kahrizi 4,  Vincent Laugel 5,  Elise Schaefer 6,  Anne de Saint Martin 7,  Karen Runge 1,  Zafar Iqbal 8,  Marie-Aude Spitz 5,  Mary Laura 9,  Nathalie Drouot 1,  Bénédicte Gérard 9,  Jean-François Deleuze 10,  Arjan P M de Brouwer 11,  Attia Razzaq 12,  Hélène Dollfus 6,  Muhammad Zaman Assir 13,  Patrick Nitchké 14,  Maria-Victoria Hinckelmann 1,  Hilger Ropers 15,  Sheikh Riazuddin 13,  Hossein Najmabadi 4,  Hans van Bokhoven 11,  Jamel Chelly 16
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
  • 2 Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
  • 3 Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan.
  • 4 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, 1985713834 Tehran, Iran.
  • 5 Department of Pediatrics, Strasbourg University Hospital, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France.
  • 6 Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
  • 7 Department of Pediatrics, Strasbourg University Hospital, 67000 Strasbourg, France.
  • 8 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Oslo University Hospital, 0450 Oslo, Norway.
  • 9 Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France.
  • 10 Centre National de Génotypage (CNG), 91000 Evry, France.
  • 11 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 12 Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan.
  • 13 Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Allama Iqbal Medical College, University of Health Sciences, 54000 Lahore, Pakistan.
  • 14 Institut Imagine, Bioinformatics Platform, Université Paris Descartes, 75015 Paris, France.
  • 15 Max-Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 16 Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France. Electronic address: chelly@igbmc.fr.
PMID: 28823707 DOI: 10.1016/j.ajhg.2017.07.010
Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing Endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

Keywords

TBC1D23; microcephaly; pontocerebellar hypoplasia; small normally proportioned cerebellum.

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