IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms8623.html
   My bibliography  Save this article

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

Author

Listed:
  • Isabelle Thiffault

    (McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center
    Service de Génétique, Centre Hospitalier Universitaire Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine
    Center for Pediatric Genomic Medicine, Children’s Mercy Hospital)

  • Nicole I. Wolf

    (VU University Medical Center, Neuroscience Campus Amsterdam)

  • Diane Forget

    (Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM))

  • Kether Guerrero

    (McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center)

  • Luan T. Tran

    (McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center)

  • Karine Choquet

    (Neurogenetics of Motion Laboratory, Montreal Neurological Institute)

  • Mathieu Lavallée-Adam

    (The Scripps Research Institute)

  • Christian Poitras

    (Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM))

  • Bernard Brais

    (Neurogenetics of Motion Laboratory, Montreal Neurological Institute)

  • Grace Yoon

    (the Hospital for Sick Children, University of Toronto)

  • Laszlo Sztriha

    (Faculty of Medicine, University of Szeged)

  • Richard I. Webster

    (The Children’s Hospital at Westmead
    Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead)

  • Dagmar Timmann

    (University Clinic Essen, University of Duisburg-Essen)

  • Bart P. van de Warrenburg

    (Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center)

  • Jürgen Seeger

    (Deutsche KlinikfürDiagnostik)

  • Alíz Zimmermann

    (Faculty of Medicine, University of Szeged)

  • Adrienn Máté

    (Faculty of Medicine, University of Szeged)

  • Cyril Goizet

    (Service de Génétique, Hôpital Pellegrin, CHU Bordeaux and University Bordeaux, Laboratoire MRGM (EA4576))

  • Eva Fung

    (The Chinese University of Hong Kong, Prince of Wales Hospital)

  • Marjo S. van der Knaap

    (VU University Medical Center, Neuroscience Campus Amsterdam)

  • Sébastien Fribourg

    (Université de Bordeaux, Institut Européen de Chimie et Biologie, ARNA Laboratory
    Institut National de la Santé Et de la Recherche Médicale, INSERM—U869, ARNA Laboratory)

  • Adeline Vanderver

    (Center for Genetic Medicine Research, Children’s National
    Children’s National
    George Washington University, School of Medicine)

  • Cas Simons

    (Institute for Molecular Bioscience, University of Queensland)

  • Ryan J. Taft

    (George Washington University, School of Medicine
    Institute for Molecular Bioscience, University of Queensland
    School of Medicine and Health Sciences, The George Washington University
    Illumina Inc.)

  • John R. Yates III

    (The Scripps Research Institute)

  • Benoit Coulombe

    (Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM)
    Université de Montréal, Pavillon Roger-Gaudry)

  • Geneviève Bernard

    (McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center)

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.

Suggested Citation

  • Isabelle Thiffault & Nicole I. Wolf & Diane Forget & Kether Guerrero & Luan T. Tran & Karine Choquet & Mathieu Lavallée-Adam & Christian Poitras & Bernard Brais & Grace Yoon & Laszlo Sztriha & Richard, 2015. "Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8623
    DOI: 10.1038/ncomms8623
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms8623
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms8623?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8623. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.