Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.
Nat Commun. 2015-07-07; 6(1):
DOI: 10.1038/ncomms8623
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1. Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.
Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of
RNA polymerase III.
Thiffault I(1), Wolf NI(2), Forget D(3), Guerrero K(4), Tran LT(4), Choquet K(5),
Lavallée-Adam M(6), Poitras C(3), Brais B(5), Yoon G(7), Sztriha L(8), Webster
RI(9), Timmann D(10), van de Warrenburg BP(11), Seeger J(12), Zimmermann A(8),
Máté A(13), Goizet C(14), Fung E(15), van der Knaap MS(2), Fribourg S(16),
Vanderver A(17), Simons C(18), Taft RJ(19), Yates JR 3rd(6), Coulombe B(20),
Bernard G(4).
Author information:
(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.
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.
DOI: 10.1038/ncomms8623
PMCID: PMC4506509
PMID: 26151409 [Indexed for MEDLINE]