Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy

Jeng Hung Wu, Jorn Hon Liu, Yu Chieh Ko, C. T.Chi Tang Wang, Yu Chien Chung, Kuo Chang Chu, Tze Tze Liu, Hsiao Ming Chao, Yun Jin Jiang*, Shih Jen Chen, Ming Yi Chung

*此作品的通信作者

研究成果: Article同行評審

54 引文 斯高帕斯(Scopus)

摘要

Familial exudative vitreoretinopathy (FEVR) belongs to a group of genetically and clinically heterogeneous disorders in retinal vascular development. To date, in approximately 50% of patients with FEVR, pathogenic mutations have been detected in FZD4, LRP5, TSPAN12, NDP and ZNF408. In this study, we identified two heterozygous frameshift mutations in RCBTB1 from three Taiwanese cases through exome sequencing. In patient-derived lymphoblastoid cell lines (LCLs), the protein level of RCBTB1 is approximately half that ofunaffected control LCLs,which is indicative of a haploinsufficiencymechanism. Byemploying transient transfection and reporter assays for the transcriptional activity of β-catenin, we demonstrated that RCBTB1 participates in the Norrin/FZD4 signaling pathway and that knockdown of RCBTB1 by shRNA significantly reduced nuclear accumulation of β-catenin under Norrin and Wnt3a treatments. Furthermore, transgenic fli1:EGFP zebrafish with rcbtb1 knockdown exhibited anomalies in intersegmental and intraocular vessels. These results strongly support that reduced RCBTB1 expression may lead to defects in angiogenesis through the Norrin-dependent Wnt pathway, and that RCBTB1 is a putative genetic cause of vitreoretinopathies.

原文English
文章編號ddw041
頁(從 - 到)1637-1647
頁數11
期刊Human Molecular Genetics
25
發行號8
DOIs
出版狀態Published - 15 4月 2016

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