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

  1. Christian Kubisch1,19,21
  1. 1Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany;
  2. 2Gene Center Munich and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, 81377 Munich, Germany;
  3. 3Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
  4. 4Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA;
  5. 5Serviço de Genética, Departamento de Pediatria, Hospital S. Maria, CHLN, 1649-035 Lisboa, Portugal;
  6. 6Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland;
  7. 7Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany;
  8. 8Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  9. 9Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy;
  10. 10Department of Neonatology, Sapienza University, 00161 Rome, Italy;
  11. 11IRCCS Casa Sollievo Della Sofferenza, Medical Genetics Unit, 71013 San Giovanni Rotondo, Italy;
  12. 12PhD Program, Molecular Genetics applied to Medical Sciences, University of Brescia, 25121 Brescia, Italy;
  13. 13U.O. Malattie Metaboliche PO Giovanni XXIII, AOU Policlinico Consorziale, 70120 Bari, Italy;
  14. 14Genomic Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, United Kingdom;
  15. 15Institute for Human Genetics, University of Cologne, 50931 Cologne, Germany;
  16. 16Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany;
  17. 17Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany;
  18. 18Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, 37077 Göttingen, Germany;
  19. 19Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
  1. Corresponding author: guntram.borck{at}uni-ulm.de

  1. ↵20 These authors contributed equally to this work.

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.

Footnotes

  • Received April 8, 2014.
  • Accepted November 26, 2014.

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/.

Articles citing this article

  • RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS medRxiv January 12, 2024 0: 2024.01.09.23300329v1-2024.01.09.23300329
  • Transcription factor binding sites are frequently under accelerated evolution in primates bioRxiv May 2, 2022 0: 2022.04.29.490094v1-2022.04.29.490094
  • Maf1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass bioRxiv November 12, 2021 0: 2021.11.09.467887v1-2021.11.09.467887
  • Functions of paralogous RNA polymerase III subunits POLR3G and POLR3GL in mouse development Proc. Natl. Acad. Sci. USA July 7, 2020 117: 15702-15711
  • RNA polymerase III transcription as a disease factor Genes Dev. July 1, 2020 34: 865-882
  • The PLATZ Transcription Factor GL6 Affects Grain Length and Number in Rice Plant Physiol. August 1, 2019 180: 2077-2090
  • Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200 J Biol Chem May 3, 2019 294: 7445-7459
  • Defective RNA Polymerase III is negatively regulated by the SUMO-Ubiquitin-Cdc48 Pathway bioRxiv March 31, 2019 0: 259846v1-259846
  • Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia bioRxiv March 5, 2019 0: 052209v1-52209
  • RNF12 catalyzes BRF1 ubiquitination and regulates RNA polymerase III-dependent transcription J Biol Chem January 4, 2019 294: 130-141
  • Mutations in MYO1H cause a recessive form of central hypoventilation with autonomic dysfunction J. Med. Genet. November 1, 2017 54: 754-761
  • The Maize Imprinted Gene Floury3 Encodes a PLATZ Protein Required for tRNA and 5S rRNA Transcription through Interaction with RNA Polymerase III Plant Cell October 1, 2017 29: 2661-2675
  • RNA polymerase III component Rpc9 regulates hematopoietic stem and progenitor cell maintenance in zebrafish Development June 15, 2016 143: 2103-2110
  • A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay Cold Spring Harb Mol Case Stud March 1, 2016 2: a000703
  • Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction Circ Cardiovasc Genet August 1, 2015 8: 544-552
| Table of Contents

This Article

  1. Published in Advance January 5, 2015, doi: 10.1101/gr.176925.114 Genome Res. 25: 155-166 © 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press

Article Category

Share

Preprint Server



Current Issue

  1. January 2026, 36 (1)
  1. Current Issue
  1. Alert me to new issues of Genome Research