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ZFIN ID: ZDB-PUB-160226-13
Haploinsufficiency of RCBTB1 is Associated with Coats Disease and Familial Exudative Vitreoretinopathy
Wu, J.H., Liu, J.H., Ko, Y.C., Wang, C.T., Chung, Y.C., Chu, K.C., Liu, T.T., Chao, H.M., Jiang, Y.J., Chen, S.J., Chung, M.Y.
Date: 2016
Source: Human molecular genetics   25(8): 1637-47 (Journal)
Registered Authors: Chu, Kuo-Chang, Jiang, Yun-Jin
Keywords: none
MeSH Terms:
  • Cell Line
  • Exome
  • Eye Proteins/metabolism
  • Female
  • Frameshift Mutation
  • Genetic Predisposition to Disease
  • Guanine Nucleotide Exchange Factors/genetics*
  • Guanine Nucleotide Exchange Factors/metabolism
  • Haploinsufficiency*
  • Humans
  • Male
  • Neovascularization, Physiologic*
  • Nerve Tissue Proteins/metabolism
  • Retinal Diseases/genetics*
  • Retinal Telangiectasis/genetics*
  • Sequence Analysis, DNA/methods*
  • Taiwan
  • Wnt Signaling Pathway
PubMed: 26908610 Full text @ Hum. Mol. Genet.

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 of unaffected control LCLs, which is indicative of a haploinsufficiency mechanism. By employing 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.