TY - JOUR
T1 - Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model
AU - Lau, Marco Chi Chung
AU - Kwong, Ernest Man Lok
AU - Lai, Keng Po
AU - Li, Jing Woei
AU - Ho, Jeff Cheuk Hin
AU - Chan, Ting Fung
AU - WONG, Chris K C
AU - Jiang, Yun Jin
AU - TSE, William K F
N1 - Funding Information:
This work was supported by the Faculty Research Grant, Hong Kong Baptist University ( FRG1/12-13/044 , FRG1/13-14/010 , and FRG1/13-14/064 ) to WKF Tse; the Lee Shau Kee Donation ( LSK/1415/P06 ) to CKC Wong and WKF Tse; the Lo Kwee-Seong Biomedical Research Fund and the Lee Hysan Foundation to JW Li and TF Chan; grants from the National Health Research Institutes, Taiwan ( MG-103-PP-13 and MG-104-PP-12 ) and the Ministry of Science and Technology, Taiwan ( MOST 103-2311-B-400-001 and MOST104-2311-B-400-001 ) to JY Jiang. We would also like to thank the staff in the Zebrafish Facility of NHRI for their efforts in maintaining fish stocks. Also, we are grateful to Chien-Ming Wang and Chih-Hao Tang for their technical help.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Cleft palate
KW - Craniofacial development
KW - Disease model
KW - Transcritpomic
UR - http://www.scopus.com/inward/record.url?scp=84962881222&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2016.03.005
DO - 10.1016/j.bbadis.2016.03.005
M3 - Journal article
AN - SCOPUS:84962881222
SN - 0925-4439
VL - 1862
SP - 1147
EP - 1158
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 6
ER -