Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model
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AbstractTreacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D, which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway. (C) 2016 Elsevier B.V. All rights reserved.
All Author(s) ListLau MCC, Kwong EML, Lai KP, Li JW, Ho JCH, Chan TF, Wong CKC, Jiang YJ, Tse WKF
Journal nameBBA - Molecular Basis of Disease
Year2016
Month6
Day1
Volume Number1862
Issue Number6
PublisherELSEVIER SCIENCE BV
Pages1147 - 1158
ISSN0925-4439
eISSN0006-3002
LanguagesEnglish-United Kingdom
KeywordsCleft palate; Craniofacial development; Disease model; Transcritpomic
Web of Science Subject CategoriesBiochemistry & Molecular Biology; Biophysics; Cell Biology

Last updated on 2020-11-08 at 03:51