ArticleGenome research2015
BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.
Article in Genome research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 104 citations in OpenAlex.
- Association Between Maternal Gestational Diabetes, Cord Blood DNA Methylation, and Offspring Neurodevelopment.International journal of molecular sciences · 2026Article
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- Genetic Insights in Hindbrain Abnormalities Through Network Analysis Expose Key Biological Pathways in Hindbrain Development.Cerebellum (London, England) · 2025Article
- Biallelic BRF2 mutations disrupt redox homeostasis as etiological factors in syndromic immunodeficiency and developmental disorders.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Bi-allelic deleterious variants in SNAPIN, which encodes a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder.American journal of human genetics · 2025Article
- Methylome-wide association study of multidimensional resilience.Development and psychopathology · 2025Article
- Deepening the Modulatory Activity of Bioactive Compounds Against AFB1- and OTA-Induced Neuronal Toxicity Through a Proteomic Approach.Antioxidants (Basel, Switzerland) · 2025Article
- Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies.Genome medicine · 2025Article
- RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.Nature communications · 2025Article
- Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Dysfunction of Small-Conductance CaCells · 2024Article
- Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.Scientific reports · 2024Article
- Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.Human genetics · 2024Article
- BDP1 as a biomarker in serous ovarian cancer.Cancer medicine · 2023Article
- RNA Polymerases I and III in development and disease.Seminars in cell & developmental biology · 2023Review
- Transcription factor binding sites are frequently under accelerated evolution in primates.Nature communications · 2023Article
- The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- tRNA dysregulation and disease.Nature reviews. Genetics · 2022Review
- One Host-Multiple Applications: Zebrafish (International journal of molecular sciences · 2022Review
1 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
25 authors at 14 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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