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

Marco Chi Chung Lau, Ernest Man Lok Kwong, Keng Po Lai, Jing Woei Li, Jeff Cheuk Hin Ho, Ting Fung Chan, Chris Kong Chu Wong, Yun Jin Jiang, William Ka Fai Tse

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Treacher 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.

Original languageEnglish
Pages (from-to)1147-1158
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1862
Issue number6
DOIs
Publication statusPublished - Jun 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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