Borck, Guntram, Hog, Friederike, Dentici, Maria Lisa, Tan, Perciliz L., Sowada, Nadine, Medeira, Ana, Gueneau, Lucie, Thiele, Holger, Kousi, Maria, Lepri, Francesca, Wenzeck, Larissa, Blumenthal, Ian, Radicioni, Antonio, Schwarzenberg, Tito Livio, Mandriani, Barbara ORCID: 0000-0002-4139-0602, Fischetto, Rita, Morris-Rosendahl, Deborah J., Altmuller, Janine, Reymond, Alexandre, Nurnberg, Peter, Merla, Giuseppe, Dallapiccola, Bruno ORCID: 0000-0002-5031-1013, Katsanis, Nicholas ORCID: 0000-0002-2480-0171, Cramer, Patrick and Kubisch, Christian ORCID: 0000-0003-4220-0978 (2015). BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. Genome Res., 25 (2). S. 155 - 167. COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 1549-5469

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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 bif1 in zebraflsh 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hog, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dentici, Maria LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Perciliz L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sowada, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medeira, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gueneau, LucieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kousi, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lepri, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzeck, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blumenthal, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radicioni, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarzenberg, Tito LivioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mandriani, BarbaraUNSPECIFIEDorcid.org/0000-0002-4139-0602UNSPECIFIED
Fischetto, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris-Rosendahl, Deborah J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reymond, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merla, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dallapiccola, BrunoUNSPECIFIEDorcid.org/0000-0002-5031-1013UNSPECIFIED
Katsanis, NicholasUNSPECIFIEDorcid.org/0000-0002-2480-0171UNSPECIFIED
Cramer, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
URN: urn:nbn:de:hbz:38-413938
DOI: 10.1101/gr.176925.114
Journal or Publication Title: Genome Res.
Volume: 25
Number: 2
Page Range: S. 155 - 167
Date: 2015
Publisher: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication: COLD SPRING HARBOR
ISSN: 1549-5469
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
POL III; INTELLECTUAL DISABILITY; COMPLEX; TFIIB; VARIANTS; AUTISM; PHENOTYPES; SUBUNIT; CANCER; ATAXIAMultiple languages
Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41393

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