TY  - JOUR
A1  - Borck, Guntram
A1  - Hög, Friederike
A1  - Dentici, Maria Lisa
A1  - Tan, Perciliz L.
A1  - Sowada, Nadine
A1  - Medeira, Ana
A1  - Gueneau, Lucie
A1  - Thiele, Holger
A1  - Kousi, Maria
A1  - Lepri, Francesca
A1  - Wenzeck, Larissa
A1  - Blumenthal, Ian
A1  - Radicioni, Antonio
A1  - Schwarzenberg, Tito Livio
A1  - Mandriani, Barbara
A1  - Fischetto, Rita
A1  - Morris-Rosendahl, Deborah J.
A1  - Altmüller, Janine
A1  - Reymond, Alexandre
A1  - Nürnberg, Peter
A1  - Merla, Giuseppe
A1  - Dallapiccola, Bruno
A1  - Katsanis, Nicholas
A1  - Cramer, Patrick
A1  - Kubisch, Christian
T1  - BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies
Y1  - 2015/02/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 155 
EP  - 166 
DO  - 10.1101/gr.176925.114 
VL  - 25 
IS  - 2 
UR  - http://genome.cshlp.org/content/25/2/155.abstract 
N2  - 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. 
ER  -