2. Academic Validation
  3. Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

  • Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.
Isabelle Thiffault 1,  Nicole I Wolf 2,  Diane Forget 3,  Kether Guerrero 4,  Luan T Tran 4,  Karine Choquet 5,  Mathieu Lavallée-Adam 6,  Christian Poitras 3,  Bernard Brais 5,  Grace Yoon 7,  Laszlo Sztriha 8,  Richard I Webster 9,  Dagmar Timmann 10,  Bart P van de Warrenburg 11,  Jürgen Seeger 12,  Alíz Zimmermann 8,  Adrienn Máté 13,  Cyril Goizet 14,  Eva Fung 15,  Marjo S van der Knaap 2,  Sébastien Fribourg 16,  Adeline Vanderver 17,  Cas Simons 18,  Ryan J Taft 19,  John R Yates 3rd 6,  Benoit Coulombe 20,  Geneviève Bernard 4
Affiliations

Affiliations

  • 1 1] Department of Neurology and Neurosurgery, McGill University, Department of Medical Genetics, Montreal Children's Hospital, Research Institute of the McGill University Health Center, 1001 boul Décarie, Montreal, Quebec H4A 3J1, Canada. [2] Service de Génétique, Centre Hospitalier Universitaire Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T1C5, Canada. [3] Center for Pediatric Genomic Medicine, Children's Mercy Hospital, 2420 Pershing Road, Suite 421, Kansas City, Missouri 64108, USA.
  • 2 Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands.
  • 3 Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins ouest, Montréal, Québec H2W 1R7, Canada.
  • 4 Department of Neurology and Neurosurgery, McGill University, Department of Medical Genetics, Montreal Children's Hospital, Research Institute of the McGill University Health Center, 1001 boul Décarie, Montreal, Quebec H4A 3J1, Canada.
  • 5 Neurogenetics of Motion Laboratory, Montreal Neurological Institute, 3801 University Street, McGill University, Montreal, Quebec H3A 2B4, Canada.
  • 6 Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road SR302, La Jolla, California 92037, USA.
  • 7 Division of Neurology and Clinical and Metabolic Genetics, the Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
  • 8 Department of Paediatrics, Faculty of Medicine, University of Szeged, Temesvári krt. 35-37, Szeged H-6726, Hungary.
  • 9 1] T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia. [2] Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead New South Wales 2145, Australia.
  • 10 Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
  • 11 Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
  • 12 Department of Pediatrics and Adolescent Medicine, Deutsche KlinikfürDiagnostik, Wiesbaden 65191, Germany.
  • 13 Department of Neurosurgery, Faculty of Medicine, University of Szeged, 6 Semmelweis Street, Szeged H-6725, Hungary.
  • 14 Service de Génétique, Hôpital Pellegrin, CHU Bordeaux and University Bordeaux, Laboratoire MRGM (EA4576), Bordeaux 33076, France.
  • 15 Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR China.
  • 16 1] Université de Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory, Pessac F-33607, France. [2] Institut National de la Santé Et de la Recherche Médicale, INSERM-U869, ARNA Laboratory, Bordeaux F-33000, France.
  • 17 1] Center for Genetic Medicine Research, Children's National, 111 Michigan Avenue Northwest, Washington, District of Columbia 20010, USA. [2] Department of Neurology, Children's National, 111 Michigan Avenue Northwest, Washington, District of Columbia 20010, USA. [3] George Washington University, School of Medicine, Washington, District of Columbia 20052, USA.
  • 18 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
  • 19 1] George Washington University, School of Medicine, Washington, District of Columbia 20052, USA. [2] Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. [3] Departments of Integrative Systems Biology and Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia 20037, USA. [4] Illumina Inc., 5200 Illumina Way, San Diego, California 92122, USA.
  • 20 1] Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins ouest, Montréal, Québec H2W 1R7, Canada. [2] Department of Biochemistry, Université de Montréal, Pavillon Roger-Gaudry, CP 6128, Succ Centre-Ville, Montreal, Québec H3C 3J7, Canada.
PMID: 26151409 DOI: 10.1038/ncomms8623
Abstract

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some LIGHT on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.

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