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

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 I. Webster, Dagmar Timmann, Bart P. van de Warrenburg, Jürgen Seeger, Alíz Zimmermann, Adrienn Máté, Cyril Goizet, Eva Fung, Marjo S. van der Knaap, Sébastien Fribourg, Adeline Vanderver, Cas Simons, Ryan J. Taft, John R. Yates, Benoit Coulombe () and Geneviève Bernard ()
Additional contact information
Isabelle Thiffault: McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center
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
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
Adeline Vanderver: Center for Genetic Medicine Research, Children’s National
Cas Simons: Institute for Molecular Bioscience, University of Queensland
Ryan J. Taft: George Washington University, School of Medicine
John R. Yates: The Scripps Research Institute
Benoit Coulombe: Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM)
Geneviève Bernard: McGill University, Montreal Children's Hospital, Research Institute of the McGill University Health Center

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8623

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