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

Thiffault, Isabelle, Wolf, Nicole I., Forget, Diane, Guerrero, Kether, Tran, Luan T., Choquet, Karine, Lavallee-Adam, Mathieu, Poitras, Christian, Brais, Bernard, Yoon, Grace, Sztriha, Laszlo, Webster, Richard I., Timmann, Dagmar, van de Warrenburg, Bart P., Seeger, Jurgen, Zimmermann, Aliz, Mate, Adrienn, Goizet, Cyril, Fung, Eva, van der Knaap, Marjo S., Fribourg, Sebastien, Vanderver, Adeline, Simons, Cas, Taft, Ryan J., Yates III, John R., Coulombe, Benoit and Bernard, Genevieve (2015) Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature Communications, 6 7623: 1-9. doi:10.1038/ncomms8623

Related Publications and Datasets
Author Thiffault, Isabelle
Wolf, Nicole I.
Forget, Diane
Guerrero, Kether
Tran, Luan T.
Choquet, Karine
Lavallee-Adam, Mathieu
Poitras, Christian
Brais, Bernard
Yoon, Grace
Sztriha, Laszlo
Webster, Richard I.
Timmann, Dagmar
van de Warrenburg, Bart P.
Seeger, Jurgen
Zimmermann, Aliz
Mate, Adrienn
Goizet, Cyril
Fung, Eva
van der Knaap, Marjo S.
Fribourg, Sebastien
Vanderver, Adeline
Simons, Cas
Taft, Ryan J.
Yates III, John R.
Coulombe, Benoit
Bernard, Genevieve
Title Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2015-07-07
Year available 2015
Sub-type Article (original research)
DOI 10.1038/ncomms8623
Open Access Status DOI
Volume 6
Issue 7623
Start page 1
End page 9
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 91211005
MOP G 287547
P41 GM103533
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 27 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 30 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 28 Jul 2015, 10:24:07 EST by System User on behalf of Institute for Molecular Bioscience