Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins Syndrome

Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 01/2011; 43(1):20-2. DOI: 10.1038/ng.724
Source: PubMed


We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy.

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Available from: Adriana Jeannette M Hoogeboom, Jun 27, 2014
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    • "In humans, several facial dysostoses have been linked to RNA metabolism and transport: Treacher Collins syndrome (TCS, MIM 154500) is characterised by general cranioskeletal hypoplasia due to generation of insufficient neural crest cells [Trainor et al., 2009]. Loss-of-function mutations have been identified in TCOF1, POLR1C and POLR1D which encode the nucleolar phosphoprotein Treacle, and subunits of RNA polymerase I and RNA polymerase III, respectively [Dauwerse et al., 2011; Valdez et al., 2004]. This implicates each of these genes in ribosome biogenesis in the highly proliferative neuro-epithelial and neural crest cells. "
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    ABSTRACT: Pierre Robin sequence (PRS) is an etiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ∼2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.
    European Journal of Medical Genetics 10/2014; 57(10). DOI:10.1016/j.ejmg.2014.08.007 · 1.47 Impact Factor
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    • "Treacher Collins syndrome (TCS, OMIM 154500) is a rare congenital disorder of craniofacial development affecting 1 in 50 000 live births [1]. The disorder most commonly arises from mutations of the TCOF1 gene encoding for the treacle protein, which is essential for craniofacial development [2]. TCOF1 mutations are inherited in an autosomal dominant manner, but approximately 60% are de novo mutations [1]. "
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    ABSTRACT: Treacher Collins syndrome (TCS, OMIM 154500) is a rare congenital disorder of craniofacial development. Characteristic hypoplastic malformations of the ears, zygomatic arch, mandible and pharynx have been described in detail. However, reports on the impact of these malformations on speech are few. Exploring speech features and investigating if speech function is related to phenotypic severity are essential for optimizing follow-up and treatment. Articulation, nasal resonance, voice and intelligibility were examined in 19 individuals (5-74 years, median 34 years) divided into three groups comprising children 5-10 years (n = 4), adolescents 11-18 years (n = 4) and adults 29 years and older (n = 11). A speech composite score (0-6) was calculated to reflect the variability of speech deviations. TCS severity scores of phenotypic expression and total scores of Nordic Orofacial Test-Screening (NOT-S) measuring orofacial dysfunction were used in analyses of correlation with speech characteristics (speech composite scores). Children and adolescents presented with significantly higher speech composite scores (median 4, range 1-6) than adults (median 1, range 0-5). Nearly all children and adolescents (6/8) displayed speech deviations of articulation, nasal resonance and voice, while only three adults were identified with multiple speech aberrations. The variability of speech dysfunction in TCS was exhibited by individual combinations of speech deviations in 13/19 participants. The speech composite scores correlated with TCS severity scores and NOT-S total scores. Speech composite scores higher than 4 were associated with cleft palate. The percent of intelligible words in connected speech was significantly lower in children and adolescents (median 77%, range 31-99) than in adults (98%, range 93-100). Intelligibility of speech among the children was markedly inconsistent and clearly affecting the understandability. Multiple speech deviations were identified in children, adolescents and a subgroup of adults with TCS. Only children displayed markedly reduced intelligibility. Speech was significantly correlated with phenotypic severity of TCS and orofacial dysfunction. Follow-up and treatment of speech should still be focused on young patients, but some adults with TCS seem to require continuing speech and language pathology services.
    BMC Medical Genetics 04/2014; 15(1):47. DOI:10.1186/1471-2350-15-47 · 2.08 Impact Factor
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    • "mutations in RNA polymerases I and III, providing further evidence that TCS is a neurocristopathic ribosomopathy (Dauwerse et al., 2011). Specifically, both heterozygous and homozygous carriers of mutant alleles in POL1RC and POL1RD were detected that displayed symptoms of TCS but did not express the mutant treacle protein (Dauwerse et al., 2011). Finally, it has been demonstrated that both genetic and pharmacological inactivation of Tp53 is capable of ameliorating the phenotypic defects associated with TCS via reduction of cyclin-G1 mediated cell cycle arrest and a reduction in Tp53 driven cell death of NCCs (Jones et al., 2008). "
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    ABSTRACT: Neural crest cells (NCCs) are a transient, migratory cell population, which originates during neurulation at the neural folds and contributes to the majority of tissues, including the mesenchymal structures of the craniofacial skeleton. The deregulation of the complex developmental processes that guide migration, proliferation, and differentiation of NCCs may result in a wide range of pathological conditions grouped together as neurocristopathies. Recently, due to their multipotent properties neural crest stem cells have received considerable attention as a possible source for stem cell based regenerative therapies. This exciting prospect underlines the need to further explore the developmental programs that guide NCC differentiation. This review explores the particular importance of ribosome biogenesis defects in this context since a specific interface between ribosomopathies and neurocristopathies exists as evidenced by disorders such as Treacher-Collins-Franceschetti syndrome (TCS) and Diamond-Blackfan anemia (DBA).
    Frontiers in Physiology 02/2014; 5:26. DOI:10.3389/fphys.2014.00026 · 3.53 Impact Factor
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