Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treacher Collins syndrome (TCS) is characterized by defects in craniofacial development, which results from mutations in the TCOF1 gene. TCOF1 encodes the nucleolar phosphoprotein treacle, which interacts with upstream binding factor (UBF) and affects transcription of the ribosomal DNA gene. The present study shows participation of treacle in the 2'-O-methylation of pre-rRNA. Antisense-mediated down-regulation of treacle expression in Xenopus laevis oocytes reduced 2'-O-methylation of pre-rRNA. Analysis of RNA isolated from wild-type and Tcof1+/- heterozygous mice embryos from strains that exhibit a lethal phenotype showed significant reduction in 2'-O-methylation at nucleotide C463 of 18S rRNA. The level of pseudouridylation of U1642 of 18S rRNA from the same RNA samples was not affected suggesting specificity. There is no significant difference in rRNA methylation between wild-type and heterozygous embryos of DBA x BALB/c mice, which have no obvious craniofacial phenotype. The function of treacle in pre-rRNA methylation is most likely mediated by its direct physical interaction with NOP56, a component of the ribonucleoprotein methylation complex. Although treacle co-localizes with UBF throughout mitosis, it co-localizes with NOP56 and fibrillarin, a putative methyl transferase, only during telophase when rDNA gene transcription and pre-rRNA methylation are known to commence. These observations suggest that treacle might link RNA polymerase I-catalyzed transcription and post-transcriptional modification of pre-rRNA. We hypothesize that haploinsufficiency of treacle in TCS patients results in inhibition of production of properly modified mature rRNA in addition to inhibition of rDNA gene transcription, which consequently affects proliferation and proper differentiation of specific embryonic cells during development.
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PMID:The Treacher Collins syndrome (TCOF1) gene product is involved in pre-rRNA methylation. 1593 15

Mutations in treacle lead to Treacher Collins syndrome (TCS), an autosomal dominant disorder of craniofacial development. Treacle associates with upstream binding factor (UBF) to regulate rRNA gene (rDNA) transcription, but the precise mechanisms mediated by treacle remain elusive. Here we show that the central repeated domain of treacle binds with RNA polymerase I (Pol I), while that the treacle C-terminus is involved in rDNA promoter recognition and UBF recruitment. Knockdown of treacle resulted in dispersion of Pol I and UBF away from nucleolus, whereas interactions of treacle with Pol I and rDNA promoter were not disrupted by UBF depletion. These findings indicate that treacle, but not UBF, is essential for nucleolar recruitment of Pol I transcription complex. Furthermore, C-terminally truncated treacle, mimicking TCS-associated mutations, failed to target to the nucleolus, possibly causing loss-of-function in the mutant treacle. Our observations support that TCS results from haploinsufficiency of treacle.
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PMID:Treacle recruits RNA polymerase I complex to the nucleolus that is independent of UBF. 1952 88

Treacher Collins syndrome (TCS) is a type of mandibulofacial dysostosis with incomplete penetrance and high intra- and interfamilial clinical heterogeneity, and it is associated with mutations of treacle ribosome biogenesis factor 1 (TCOF1), and RNA polymerase I and III subunit (POLR1)C and POLR1D genes. In the present case report, a patient with TCS with auricle dysplasia and hearing loss accompanied with intellectual disability is described. Sequence analysis was performed on blood samples from the patient and his father via oligonucleotide-based target capture, followed by next-generation sequencing. Alignment and variant calls were generated using the Burrows-Wheeler Aligner and Genome Analysis Toolkit, followed by bioinformatics analysis of the detected variants. A novel heterozygous mutation, c.911C>T (p.Ser304Leu), was detected in the TCOF1 gene, which was inherited from the father. The father of the patient only suffered from hearing loss. The present report is the first to identify an association between phenotypic variability and TCOF1 gene mutations and thus contributes to our understanding of the association between the genotype and phenotype in patients with TCS and offers clinically relevant information for diagnosis of the syndrome.
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PMID:A novel familial mutation associated with Treacher Collins syndrome: A case report. 3225 92