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Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.

ABSTRACT: Treacher Collins Syndrome (TCS) is a rare congenital disease (1:50?000 live births) characterized by craniofacial defects, including hypoplasia of facial bones, cleft palate and palpebral fissures. Over 90% of the cases are due to mutations in the TCOF1 gene, which codifies the nucleolar protein Treacle. Here we report a novel TCS-like zebrafish model displaying features that fully recapitulate the spectrum of craniofacial abnormalities observed in patients. As it was reported for a Tcof1+/- mouse model, Treacle depletion in zebrafish caused reduced rRNA transcription, stabilization of Tp53 and increased cell death in the cephalic region. An increase of ROS along with the overexpression of redox-responsive genes was detected; furthermore, treatment with antioxidants ameliorated the phenotypic defects of craniofacial anomalies in TCS-like larvae. On the other hand, Treacle depletion led to a lowering in the abundance of Cnbp, a protein required for proper craniofacial development. Tcof1 knockdown in transgenic zebrafish overexpressing cnbp resulted in barely affected craniofacial cartilage development, reinforcing the notion that Cnbp has a role in the pathogenesis of TCS. The cnbp overexpression rescued the TCS phenotype in a dose-dependent manner by a ROS-cytoprotective action that prevented the redox-responsive genes' upregulation but did not normalize the synthesis of rRNAs. Finally, a positive correlation between the expression of CNBP and TCOF1 in mesenchymal cells from both control and TCS subjects was found. Based on this, we suggest CNBP as an additional target for new alternative therapeutic treatments to reduce craniofacial defects not only in TCS but also in other neurocristopathies.

SUBMITTER: de Peralta MS

PROVIDER: S-EPMC5133970 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.

de Peralta Mauro S Porcel MS Mouguelar Valeria S VS Sdrigotti María Antonella MA Ishiy Felipe A A FA Fanganiello Roberto D RD Passos-Bueno Maria R MR Coux Gabriela G Calcaterra Nora B NB

Cell death & disease 20161006 10

Treacher Collins Syndrome (TCS) is a rare congenital disease (1:50 000 live births) characterized by craniofacial defects, including hypoplasia of facial bones, cleft palate and palpebral fissures. Over 90% of the cases are due to mutations in the TCOF1 gene, which codifies the nucleolar protein Treacle. Here we report a novel TCS-like zebrafish model displaying features that fully recapitulate the spectrum of craniofacial abnormalities observed in patients. As it was reported for a Tcof1<sup>+/ ...[more]

PMID: 27711076

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Project description:BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Dataset Information

Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.

Publications

Cnbp ameliorates Treacher Collins Syndrome craniofacial anomalies through a pathway that involves redox-responsive genes.

Similar Datasets

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