Proteasomal inhibition attenuates craniofacial malformations in a zebrafish model of Treacher Collins Syndrome

Craniofacial malformations have been recorded since time immemorial. While observational studies have assisted in the recognition of syndromes, little light has been shed on the causal mechanisms which interfere with craniofacial development. Animal studies in which malformations occur spontaneously or have been induced by teratogenic agents have permitted step-by-step investigation of such common deformities as cleft lip and palate. The role of the ectomesenchymal cells of the neural crest and the possible phenomenon of disorganized spontaneous cell death are described in relation to lip clefts. The factors associated with isolated cleft palate, Pierre Robin syndrome and submucous clefts are described by reference to animal models. The haemorrhagic accident preceding the onset of craniofacial microsomia is discussed as is the distinctly different phenomenon of disturbance to the migration or differentiation of neural crest cells in the pathogenesis of Treacher Collins syndrome. The more severe anomalies of the calvarium such as plagiocephaly, Crouzon and Apert syndrome still defy explanation, in the absence of an appropriate animal system to study; some thoughts on the likely mechanism of abnormal sutural fusions are discussed.

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Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2016.03.005 ◽

2016 ◽

Vol 1862 (6) ◽

pp. 1147-1158 ◽

Cited By ~ 20

Author(s):

Marco Chi Chung Lau ◽

Ernest Man Lok Kwong ◽

Keng Po Lai ◽

Jing-Woei Li ◽

Jeff Cheuk Hin Ho ◽

...

Keyword(s):

Treacher Collins Syndrome ◽

Zebrafish Model ◽

Type 3 ◽

Dependent Type

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RNAi Knockdown of Nopp140 Induces Minute-like Phenotypes in Drosophila

Molecular Biology of the Cell ◽

10.1091/mbc.e07-01-0074 ◽

2007 ◽

Vol 18 (6) ◽

pp. 2179-2191 ◽

Cited By ~ 17

Author(s):

Zhengfang Cui ◽

Patrick J. DiMario

Keyword(s):

Phenotypic Expression ◽

Treacher Collins Syndrome ◽

Carboxy Terminus ◽

Craniofacial Malformations ◽

Reverse Transcription Pcr ◽

Adult Wing ◽

Transgenic Lines ◽

Melanotic Tumors ◽

Nuclear Structures ◽

Interfering Rna

Nopp140 associates with small nucleolar RNPs to chaperone pre-rRNA processing and ribosome assembly. Alternative splicing yields two isoforms in Drosophila: Nopp140-True is homologous to vertebrate Nopp140 particularly in its carboxy terminus, whereas Nopp140-RGG contains a glycine and arginine-rich (RGG) carboxy terminus typically found in vertebrate nucleolin. Loss of ribosome function or production at critical points in development leads to Minute phenotypes in Drosophila or the Treacher Collins syndrome (TCS) in humans. To ascertain the functional significance of Nopp140 in Drosophila development, we expressed interfering RNA using the GAL4/UAS system. Reverse transcription-PCR showed variable losses of Nopp140 mRNA in larvae from separate RNAi-expressing transgenic lines, whereas immunofluorescence microscopy with isoform-specific antibodies showed losses of Nopp140 in imaginal and polyploid tissues. Phenotypic expression correlated with the percent loss of Nopp140 transcripts: a ≥50% loss correlated with larval and pupal lethality, disrupted nuclear structures, and in some cases melanotic tumors, whereas a 30% loss correlated with adult wing, leg, and tergite deformities. We consider these adult phenotypes to be Minute-like and reminiscent of human craniofacial malformations associated with TCS. Similarly, overexpression of either isoform caused embryonic and larval lethality, thus indicating proper expression of Nopp140 is critical for normal development.

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Intraoral scanning of neonates and infants with craniofacial disorders: feasibility, scanning duration, and clinical experience

European Journal of Orthodontics ◽

10.1093/ejo/cjab068 ◽

2021 ◽

Author(s):

Christina Weise ◽

Karin Frank ◽

Cornelia Wiechers ◽

Hannes Weise ◽

Siegmar Reinert ◽

...

Keyword(s):

Success Rate ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Treacher Collins Syndrome ◽

Digital Impression ◽

Craniofacial Malformations ◽

Small Children ◽

Intraoral Scanning ◽

Significant Difference ◽

Mandibular Retrognathia

Summary Objective The aim of this study was to evaluate intraoral scanning (IOS) in infants, neonates, and small children with craniofacial anomalies for its feasibility, scanning duration, and success rate. Impression taking in vulnerable patients can be potentially life-threatening, with the risk of airway obstruction and aspiration of impression material. The advantage of increasingly digitalized dentistry is demonstrated. Materials and methods IOS was captured with the Trios 3® (3Shape, Copenhagen, Denmark) intraoral scanner. The underlying disorders were divided into cleft lip and palate (CLP), Trisomy 21 (T21), Robin Sequence (RS), Treacher Collins syndrome (TC), and isolated mandibular retrognathia (MR). Scan data were analysed by scanning duration, number of images, possible correlations of these factors with the different craniofacial disorders, patient age, and relationship between first and subsequent scans. Clinical experiences with the repeated digital impressions are described. Results Patient data of 141 scans in 83 patients were analysed within an 11-month period. Patients had a median age of 137 days. Median scanning duration was 138 seconds, resulting in a median of 352 images. There was a statistically significant difference in scanning duration (P = 0.001) between infants and neonates. IOS took longest in patients with CLP (537 seconds) and shortest in T21 patients (21 seconds), although there was no statistically significant difference between aetiologies. There was no statistically significant difference between first and subsequent scans in scanning duration. In four cases the IOS had to be repeated, and one patient ultimately required conventional impression taking (all CLP patients; success rate 94%). No severe adverse events occurred. Conclusion IOS is a fast, safe, and feasible procedure for neonates, small children, and infants with craniofacial malformations. One special challenge for both technician and user was identified in patients with CLP, though implementing this new approach of digital impression taking was otherwise found to be highly successful in everyday clinical routine.

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Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype

10.1101/281485 ◽

2018 ◽

Author(s):

Ivo J.H.M. de Vos ◽

Evelyn Yaqiong Tao ◽

Sheena Li Ming Ong ◽

Julian L. Goggi ◽

Thomas Scerri ◽

...

Keyword(s):

Functional Analysis ◽

Catalytic Activity ◽

Joint Destruction ◽

Residual Activity ◽

Published Data ◽

Craniofacial Malformations ◽

Zebrafish Model ◽

Prime Determinant ◽

Winchester Syndrome

AbstractWinchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation inMMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murineMMP14mutations, does not affect MMP14’s transport to the cell membrane. Instead, it partially impairs MMP14’s proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14’s catalytic activity is the prime determinant of disease severity. Given the limitations of ourin vitroassays in addressing the consequences of MMP14 dysfunction, we generated a novelmmp14a/bknockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density due to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.

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Evolution of a child with Treacher Collins syndrome undergoing physiotherapeutic treatment

Fisioterapia em Movimento ◽

10.1590/0103-5150.028.003.ao11 ◽

2015 ◽

Vol 28 (3) ◽

pp. 525-533 ◽

Cited By ~ 1

Author(s):

Bárbara Gabriela da S. Rodrigues ◽

Juliane Leonardo Oliveira Silva ◽

Pryscilla Gualberto Guimarães ◽

Cibelle Kayenne Martins Roberto Formiga ◽

Fabiana Pavan Viana

Keyword(s):

Motor Function ◽

Motor Development ◽

Treacher Collins Syndrome ◽

Psychomotor Development ◽

Initial Assessment ◽

Multidisciplinary Teams ◽

Craniofacial Malformations ◽

Gross Motor Function Measure ◽

Assessment Sheet ◽

Mandibulofacial Dysostosis

AbstractIntroduction Treacher Collins syndrome, or mandibulofacial dysostosis, is a hereditary disorder and is manifested by craniofacial malformations. The incidence is close to one case per 40,000 live births, without relation to gender or race. The infant carrier may present neurological development. This rare syndrome requires documentation of its main clinical and kinetic-functional consequences.Objectives The purpose of this study was to describe the clinical and kinetic-functional findings for a child who has Treacher Collins syndrome and receives treatment in the Physiotherapy Department at the Pestalozzi Association in Goiania, and to present the evolution of motor function and psychomotor development during rehabilitation.Materials and methods The information was obtained through interviews with the mother, and evaluation of the child at nine and eleven months old, using the infant neurological assessment sheet, Inventory Operational Portage (IPO) and Gross Motor Function Measure (GMFM).Results The GMFM showed that the child had a higher trend in the items for lying and rolling, sitting, crawling and kneeling and minor changes in the items for standing, walking, running and jumping. In the IPO, the child progressed in all of the assessed areas: infant stimulation, motor development, socialization, self-care, cognition and language.Conclusion The child showed progress in psychomotor development in accordance with that expected for their age and initial assessment. It is suggested that children with this syndrome be treated by multidisciplinary teams in the first years of life, preventing delays and deviations in development.

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