English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

Borck, G., Hög, F., Dentici, M. L., Tan, P. L., Sowada, N., Medeira, A., et al. (2015). BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. Genome Research, 25(2), 155-166. doi:10.1101/gr.176925.114.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-E5AD-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-9092-C
Genre: Journal Article

Files

show Files
hide Files
:
2104426.pdf (Publisher version), 2MB
Name:
2104426.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2104426_Suppl_1.pdf (Supplementary material), 24KB
Name:
2104426_Suppl_1.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2104426_Suppl_2.pdf (Supplementary material), 2MB
Name:
2104426_Suppl_2.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2104426_Suppl_3.pdf (Supplementary material), 5MB
Name:
2104426_Suppl_3.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2104426_Suppl_4.tif (Supplementary material), 74KB
Name:
2104426_Suppl_4.tif
Description:
-
Visibility:
Public
MIME-Type / Checksum:
image/tiff / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2104426_Suppl_5.doc (Supplementary material), 98KB
Name:
2104426_Suppl_5.doc
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/msword / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show
hide
Description:
-

Creators

show
hide
 Creators:
Borck, G., Author
Hög, F., Author
Dentici, M. L., Author
Tan, P. L., Author
Sowada, N., Author
Medeira, A., Author
Gueneau, L., Author
Thiele, H., Author
Kousi, M., Author
Lepri, F., Author
Wenzeck, L., Author
Blumenthal, I., Author
Radicioni, A., Author
Schwarzenberg, T. L., Author
Mandriani, B., Author
Fischetto, R., Author
Morris-Rosendahl, D. J., Author
Altmüller, J., Author
Reymond, A., Author
Nürnberg, P., Author
Merla, G., AuthorDallapiccola, B., AuthorKatsanis, N., AuthorCramer, P.1, Author              Kubisch, C., Author more..
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

Content

show
hide
Free keywords: -
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2015-01-052015-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1101/gr.176925.114
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Genome Research
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 25 (2) Sequence Number: - Start / End Page: 155 - 166 Identifier: -