BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

Item Type:	Article
Title:	BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies
Creators Name:	Borck, G. and Hög, F. and Dentici, M.L. and Tan, P.L. and Sowada, N. and Medeira, A. and Gueneau, L. and Thiele, H. and Kousi, M. and Lepri, F. and Wenzeck, L. and Blumenthal, I. and Radicioni, A. and Schwarzenberg, T.L. and Mandriani, B. and Fischetto, R. and Morris-Rosendahl, D.J. and Altmüller, J. and Reymond, A. and Nürnberg, P. and Merla, G. and Dallapiccola, B. and Katsanis, N. and Cramer, P. and Kubisch, C.
Abstract:	RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III–related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.
Keywords:	Amino Acid Sequence, Amino Acid Substitution, Brain, Cell Proliferation, Exome, Facies, Genetic Transcription, High-Throughput Nucleotide Sequencing, Intellectual Disability, Magnetic Resonance Imaging, Molecular Models, Molecular Sequence Data, Multiple Abnormalities, Mutation, Pedigree, Phenotype, Protein Conformation, Protein Isoforms, RNA Polymerase III, Siblings, Syndrome, TATA-Binding Protein Associated Factors, Animals, Zebrafish
Source:	Genome Research
ISSN:	1088-9051
Publisher:	Cold Spring Harbor Laboratory Press
Volume:	25
Number:	2
Page Range:	155-166
Date:	February 2015
Additional Information:	Erratum in: Genome Res. 2015 25(4): 609. - Copyright © 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
Official Publication:	https://doi.org/10.1101/gr.176925.114
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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