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Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

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Abstract

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13–q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13–12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13–23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in FZD4, encoding the putative Wnt receptor frizzled-4, segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca2+ signaling pathway. In one of the mutants, altered subcellular trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.

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Figure 1: Linkage and haplotype analysis.
Figure 2: Sequence chromatograms of the FZD4 mutations in FEVR.
Figure 3: Alignment of the mutant protein sequences with FZD4 and homologs from humans and other species.
Figure 4: Expression, localization and signaling of wildtype frizzled-4 and FEVR mutants.

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Change history

  • 22 August 2002

    Changed Wn to Wnt and changed vasculative to vasculature

Notes

  1. NOTE: There were two typographical errors in the AOP version of this article, which have since been corrected. On page 1, 'Wn' in line 12 was replaced with 'Wnt', and 'vasculative' in line 10 was replaced with 'vasculature'. The article will appear correctly in a forthcoming print issue.

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Acknowledgements

The authors thank J. Thompson, T. Pape, J. MacFarlane, B. Payne, C. Radomski, M. Mattice, A. Hogan, P. Samra, and G. Donaldson at Xenon Genetics and C. Tatlidil at Dalhousie University for technical support; F. Mikelberg for discussion; and the members of the affected families for their enthusiasm and participation. This work was supported in part by a grant from the Nova Scotia Health Research Foundation and the IWK Health Centre to J.R. B.S.S. was supported in part by the Fight for Sight research division of Prevent Blindness America. R.T.M. is an Investigator of the Howard Hughes Medical Institute. M.R.H. holds a Canada Research Chair. A.K. was supported by an US National Institutes of Health Reproductive Biology Training Grant.

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Correspondence to Michael R. Hayden.

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Portions of this research have been financially supported by Xenon Genetics, Inc., either directly (through research collaborations) or indirectly (as some of the authors are Xenon employees).

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Robitaille, J., MacDonald, M., Kaykas, A. et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 32, 326–330 (2002). https://doi.org/10.1038/ng957

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