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J Biol Chem
2011 Mar 25;28612:10210-5. doi: 10.1074/jbc.M110.194399.
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An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy.
Zhang K
,
Harada Y
,
Wei X
,
Shukla D
,
Rajendran A
,
Tawansy K
,
Bedell M
,
Lim S
,
Shaw PX
,
He X
,
Yang Z
.
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The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/β-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/β-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the β-catenin pathway.
Canny,
Fluorescein angiographic findings in familial exudative vitreoretinopathy.
1976, Pubmed
Canny,
Fluorescein angiographic findings in familial exudative vitreoretinopathy.
1976,
Pubmed
Chen,
A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.
1993,
Pubmed
Harland,
Formation and function of Spemann's organizer.
1997,
Pubmed
Hsieh,
Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein.
1999,
Pubmed
,
Xenbase
Junge,
TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling.
2009,
Pubmed
Karan,
Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability.
2004,
Pubmed
Kato,
Neuralization of the Xenopus embryo by inhibition of p300/ CREB-binding protein function.
1999,
Pubmed
,
Xenbase
Kaykas,
Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization.
2004,
Pubmed
Liu,
Mapping canonical Wnt signaling in the developing and adult retina.
2006,
Pubmed
Nikopoulos,
Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.
2010,
Pubmed
Nikopoulos,
Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy.
2010,
Pubmed
Osakada,
Wnt signaling promotes regeneration in the retina of adult mammals.
2007,
Pubmed
Pendergast,
Familial exudative vitreoretinopathy. Results of surgical management.
1998,
Pubmed
Pendergast,
Study of the Norrie disease gene in 2 patients with bilateral persistent hyperplastic primary vitreous.
1998,
Pubmed
Poulter,
Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy.
2010,
Pubmed
Robitaille,
Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.
2002,
Pubmed
,
Xenbase
Smallwood,
Mutational analysis of Norrin-Frizzled4 recognition.
2007,
Pubmed
,
Xenbase
Toomes,
Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.
2004,
Pubmed
van Nouhuys,
Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy.
1991,
Pubmed
Xu,
Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.
2004,
Pubmed
Ye,
Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization.
2009,
Pubmed