title: Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.
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.
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands.
authors.forename: Nicole I
authors.identifier: 0000000317210728
authors.initials: NI
authors.lastname: Wolf
authors.affiliation: Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins ouest, Montréal, Québec H2W 1R7, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Forget
authors.affiliation: 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.
authors.forename: Kether
authors.initials: K
authors.lastname: Guerrero
authors.affiliation: 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.
authors.forename: Luan T
authors.initials: LT
authors.lastname: Tran
authors.affiliation: Neurogenetics of Motion Laboratory, Montreal Neurological Institute, 3801 University Street, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Choquet
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road SR302, La Jolla, California 92037, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lavallée-Adam
authors.affiliation: Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins ouest, Montréal, Québec H2W 1R7, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Poitras
authors.affiliation: Neurogenetics of Motion Laboratory, Montreal Neurological Institute, 3801 University Street, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.affiliation: Division of Neurology and Clinical and Metabolic Genetics, the Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Szeged, Temesvári krt. 35-37, Szeged H-6726, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Sztriha
authors.affiliation: 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.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Webster
authors.affiliation: Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Deutsche KlinikfürDiagnostik, Wiesbaden 65191, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seeger
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Szeged, Temesvári krt. 35-37, Szeged H-6726, Hungary.
authors.forename: Alíz
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Szeged, 6 Semmelweis Street, Szeged H-6725, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Máté
authors.affiliation: Service de Génétique, Hôpital Pellegrin, CHU Bordeaux and University Bordeaux, Laboratoire MRGM (EA4576), Bordeaux 33076, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR China.
authors.forename: Eva
authors.initials: E
authors.lastname: Fung
authors.affiliation: Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands.
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.affiliation: 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.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fribourg
authors.affiliation: 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.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: 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.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Taft
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road SR302, La Jolla, California 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Coulombe
authors.affiliation: 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.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Bernard
mesh_terms: D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D009154:Mutation; D012320:RNA Polymerase III / Q000235:genetics / Q000378:metabolism*
chemical_list: D012321:DNA-Directed RNA Polymerases; C569283:POLR1C protein, human; D012320:RNA Polymerase III