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Treacher Collins syndrome mutations in Saccharomyces cerevisiae destabilize RNA polymerase I and III complex integrity.

ABSTRACT: Treacher Collins syndrome (TCS) is a craniofacial disorder that is characterized by the malformation of the facial bones. Mutations in three genes (TCOF1, POLR1C and POLR1D) involved in RNA polymerase I (Pol I) transcription account for more than 90% of disease cases. Two of these TCS-associated genes, POLR1C and POLR1D, encode for essential Pol I/III subunits that form a heterodimer necessary for Pol I/III assembly, and many TCS mutations lie along their evolutionarily conserved dimerization interface. Here we elucidate the molecular basis of TCS mutations in Saccharomyces cerevisiae, and present a new model for how TCS mutations may disrupt Pol I and III complex integrity.

SUBMITTER: Walker-Kopp N

PROVIDER: S-EPMC6251613 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Treacher Collins syndrome mutations in Saccharomyces cerevisiae destabilize RNA polymerase I and III complex integrity.

Walker-Kopp Nancy N Jackobel Ashleigh J AJ Pannafino Gianno N GN Morocho Paola A PA Xu Xia X Knutson Bruce A BA

Human molecular genetics 20171101 21

Treacher Collins syndrome (TCS) is a craniofacial disorder that is characterized by the malformation of the facial bones. Mutations in three genes (TCOF1, POLR1C and POLR1D) involved in RNA polymerase I (Pol I) transcription account for more than 90% of disease cases. Two of these TCS-associated genes, POLR1C and POLR1D, encode for essential Pol I/III subunits that form a heterodimer necessary for Pol I/III assembly, and many TCS mutations lie along their evolutionarily conserved dimerization in ...[more]

PMID: 28973381

Similar Datasets

Treacher Collins syndrome.

Project description:Treacher Collins syndrome (TCS) is a rare autosomal dominant disorder of craniofacial development. It is a congenital malformation of first and second branchial arch which may affect the size and shape of the ears, eyelids, cheek bones, and jaws. The extent of facial deformity varies from one affected individual to another. A case of 20-year-old boy having TCS is briefly described in this article.

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Microarray Analysis of Treacher Collins Syndrome

Project description:The object of this study was to identify genes transcriptionally upregulated and downregulated in response to Tcof1 haploin-sufficiency during mouse embryogensis Keywords: mouse embryo, littermates, Tcof1, Treacher Collins sydnrome, comparative hybridisation

2008-01-15 | GSE10167 | GEO

Novel mutations of TCOF1 gene in European patients with Treacher Collins syndrome.

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Identification of three novel TCOF1 mutations in patients with Treacher Collins Syndrome.

Project description:Here we describe three novel TCOF1 mutations found in unrelated patients with Treacher Collins syndrome. These mutations include one deletion, NM_001135243.2:c.2604_2605delAG (p.Gly869Glufs*3), and two substitutions, NM_001135243.2:c.2575C>T (p.Gln859*) and NM_001135243.2:c.4111G>T (p.Glu1371*). These mutations cause shortening of a protein called Treacle in patients with features typical of TCS. Continuous identification of new mutations is important to expand the mutation base, which is helpful in the diagnosis of both patients and their families.

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A case of treacher collins syndrome.

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Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits.

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Compromised RNA polymerase III complex assembly leads to local alterations of intergenic RNA polymerase II transcription in Saccharomyces cerevisiae.

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Treacher Collins syndrome: etiology, pathogenesis and prevention.

Project description:Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development that arises as the result of mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as Treacle. Individuals diagnosed with TCS frequently undergo multiple reconstructive surgeries, which are rarely fully corrective. Identifying potential avenues for rescue and/or repair of TCS depends on a profound appreciation of the etiology and pathogenesis of the syndrome. Recent research using animal models has not only determined the cellular basis of TCS but also, more importantly, unveiled a successful avenue for therapeutic intervention and prevention of the craniofacial anomalies observed in TCS.

| S-EPMC2986179 | biostudies-literature

The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome.

Project description:Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention.

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