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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish
Article numberddw041
Pages (from-to)1637-1647
Number of pages11
JournalHuman Molecular Genetics
Issue number8
StatePublished - 15 Apr 2016


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