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Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Nature Genetics volume 32, pages 326–330 (2002)Cite this article

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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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GenBank/EMBL/DDBJ

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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Author notes

  1. Johane Robitaille and Marcia L.E. MacDonald: These two authors contributed equally to the work.

Authors and Affiliations

  1. Department of Ophthalmology, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, B3H 2Y9, Nova Scotia, Canada

    Johane Robitaille, Duane L. Guernsey & Binyou Zheng

  2. Department of Pathology, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, B3H 4H7, Nova Scotia, Canada

    Johane Robitaille & Duane L. Guernsey

  3. Xenon Genetics, Inc., Burnaby, V5G 4W8, British Columbia, Canada

    Marcia L.E. MacDonald, Jutta Zeisler, Marie-Pierre Dubé, Lin-Hua Zhang, Roshni R. Singaraja, Simon N. Pimstone, Michael R. Hayden, Y. Paul Goldberg & Mark E. Samuels

  4. Department of Pharmacology, Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington, USA

    Ajamete Kaykas, Laird C. Sheldahl & Randall T. Moon

  5. Department of Ophthalmology, University of Western Ontario, London, Ontario, Canada

    Lee F. Siebert

  6. Department of Ophthalmology, QEII Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada

    Ann Hoskin-Mott

  7. William Beaumont Hospital, Royal Oak, Michigan, USA

    Michael T. Trese

  8. Department of Biological Sciences, Oakland University, Rochester, Michigan, USA

    Barkur S. Shastry

  9. Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1, British Columbia, Canada

    Michael R. Hayden & Y. Paul Goldberg

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  1. Johane Robitaille
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Corresponding author

Correspondence to Michael R. Hayden.

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Competing interests

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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