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.Weshow that disease-causingmutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1mutations 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

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies / Borck, Guntram; Hög, 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; Fischetto, Rita; Morris Rosendahl, Deborah J.; Altmüller, Janine; Reymond, Alexandre; Nürnberg, Peter; Merla, Giuseppe; Dallapiccola, Bruno; Katsanis, Nicholas; Cramer, Patrick; Kubisch, Christian. - In: GENOME RESEARCH. - ISSN 1088-9051. - STAMPA. - 25:2(2015), pp. 155-166. [10.1101/gr.176925.114]

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

DENTICI, MARIA LISA;RADICIONI, Antonio;SCHWARZENBERG, Tito Livio;
2015

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.Weshow that disease-causingmutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1mutations 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
2015
Abnormalities, Multiple; Adolescent; Amino Acid Sequence; Amino Acid Substitution; Animals; Brain; Cell Proliferation; Child; Child, Preschool; Exome; Facies; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Intellectual Disability; Magnetic Resonance Imaging; Male; Models, Molecular; Molecular Sequence Data; Pedigree; Phenotype; Protein Conformation; Protein Isoforms; RNA Polymerase III; Siblings; Syndrome; TATA-Binding Protein Associated Factors; Zebrafish; Mutation; Transcription, Genetic; Genetics; Genetics (clinical)
01 Pubblicazione su rivista::01a Articolo in rivista
BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies / Borck, Guntram; Hög, 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; Fischetto, Rita; Morris Rosendahl, Deborah J.; Altmüller, Janine; Reymond, Alexandre; Nürnberg, Peter; Merla, Giuseppe; Dallapiccola, Bruno; Katsanis, Nicholas; Cramer, Patrick; Kubisch, Christian. - In: GENOME RESEARCH. - ISSN 1088-9051. - STAMPA. - 25:2(2015), pp. 155-166. [10.1101/gr.176925.114]
File allegati a questo prodotto
File Dimensione Formato  
Borck_BRF1-mutations_2015.pdf

accesso aperto

Note: Articolo principale
Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.2 MB
Formato Adobe PDF
1.2 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/908282
Citazioni
  • ???jsp.display-item.citation.pmc??? 42
  • Scopus 80
  • ???jsp.display-item.citation.isi??? 82
social impact