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

Details

Serval ID
serval:BIB_BFE1C03EAD4D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.
Journal
Genome Research
Author(s)
Borck G., Hög F., Dentici M.L., Tan P.L., Sowada N., Medeira A., Gueneau L., Thiele H., Kousi M., Lepri F., Wenzeck L., Blumenthal I., Radicioni A., Schwarzenberg T.L., Mandriani B., Fischetto R., Morris-Rosendahl D.J., Altmüller J., Reymond A., Nürnberg P., Merla G., Dallapiccola B., Katsanis N., Cramer P., Kubisch C.
ISSN
1549-5469 (Electronic)
ISSN-L
1088-9051
Publication state
Published
Issued date
2015
Volume
25
Number
2
Pages
155-166
Language
english
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.
Pubmed
Web of science
Open Access
Yes
Create date
27/02/2015 10:27
Last modification date
20/08/2019 16:34
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