PortalPublikationenBRF1 mutations alter RNA polymerase III-dependent transcript...

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

Standard

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 RES, Jahrgang 25, Nr. 2, 02.2015, S. 155-66.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Borck, G, Hög, F, Dentici, ML, Tan, PL, Sowada, N, Medeira, A, Gueneau, L, Thiele, H, Kousi, M, Lepri, F, Wenzeck, L, Blumenthal, I, Radicioni, A, Schwarzenberg, TL, Mandriani, B, Fischetto, R, Morris-Rosendahl, DJ, Altmüller, J, Reymond, A, Nürnberg, P, Merla, G, Dallapiccola, B, Katsanis, N, Cramer, P & Kubisch, C 2015, 'BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies', GENOME RES, Jg. 25, Nr. 2, S. 155-66. https://doi.org/10.1101/gr.176925.114

APA

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., ... Kubisch, C. (2015). BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. GENOME RES, 25(2), 155-66. https://doi.org/10.1101/gr.176925.114

Vancouver

Borck G, Hög F, Dentici ML, Tan PL, Sowada N, Medeira A et al. BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. GENOME RES. 2015 Feb;25(2):155-66. https://doi.org/10.1101/gr.176925.114

Bibtex

@article{0bd17d5f4d9d41bbbe657f0598e8c76c,
title = "BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies",
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.",
keywords = "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, Mutation, Pedigree, Phenotype, Protein Conformation, Protein Isoforms, RNA Polymerase III, Siblings, Syndrome, TATA-Binding Protein Associated Factors, Transcription, Genetic, Zebrafish",
author = "Guntram Borck and Friederike H{\"o}g and Dentici, {Maria Lisa} and Tan, {Perciliz L} and Nadine Sowada and Ana Medeira and Lucie Gueneau and Holger Thiele and Maria Kousi and Francesca Lepri and Larissa Wenzeck and Ian Blumenthal and Antonio Radicioni and Schwarzenberg, {Tito Livio} and Barbara Mandriani and Rita Fischetto and Morris-Rosendahl, {Deborah J} and Janine Altm{\"u}ller and Alexandre Reymond and Peter N{\"u}rnberg and Giuseppe Merla and Bruno Dallapiccola and Nicholas Katsanis and Patrick Cramer and Christian Kubisch",
note = "{\textcopyright} 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press.",
year = "2015",
month = feb,
doi = "10.1101/gr.176925.114",
language = "English",
volume = "25",
pages = "155--66",
journal = "GENOME RES",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "2",

}

RIS

TY - JOUR

T1 - BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies

AU - Borck, Guntram

AU - Hög, Friederike

AU - Dentici, Maria Lisa

AU - Tan, Perciliz L

AU - Sowada, Nadine

AU - Medeira, Ana

AU - Gueneau, Lucie

AU - Thiele, Holger

AU - Kousi, Maria

AU - Lepri, Francesca

AU - Wenzeck, Larissa

AU - Blumenthal, Ian

AU - Radicioni, Antonio

AU - Schwarzenberg, Tito Livio

AU - Mandriani, Barbara

AU - Fischetto, Rita

AU - Morris-Rosendahl, Deborah J

AU - Altmüller, Janine

AU - Reymond, Alexandre

AU - Nürnberg, Peter

AU - Merla, Giuseppe

AU - Dallapiccola, Bruno

AU - Katsanis, Nicholas

AU - Cramer, Patrick

AU - Kubisch, Christian

N1 - © 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2015/2

Y1 - 2015/2

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.

AB - 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.

KW - Abnormalities, Multiple

KW - Adolescent

KW - Amino Acid Sequence

KW - Amino Acid Substitution

KW - Animals

KW - Brain

KW - Cell Proliferation

KW - Child

KW - Child, Preschool

KW - Exome

KW - Facies

KW - Female

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Infant

KW - Intellectual Disability

KW - Magnetic Resonance Imaging

KW - Male

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Protein Conformation

KW - Protein Isoforms

KW - RNA Polymerase III

KW - Siblings

KW - Syndrome

KW - TATA-Binding Protein Associated Factors

KW - Transcription, Genetic

KW - Zebrafish

U2 - 10.1101/gr.176925.114

DO - 10.1101/gr.176925.114

M3 - SCORING: Journal article

C2 - 25561519

VL - 25

SP - 155

EP - 166

JO - GENOME RES

JF - GENOME RES

SN - 1088-9051

IS - 2

ER -