Nature Genetics
32, 326 - 330 (2002)
Published online: 12 August 2002; Corrected online: 22 August 2002 | doi:10.1038/ng957
Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathyJohane Robitaille1, 2, 10, Marcia L.E. MacDonald3, 10, Ajamete Kaykas4, Laird C. Sheldahl4, Jutta Zeisler3, Marie-Pierre Dubé3, Lin-Hua Zhang3, Roshni R. Singaraja3, Duane L. Guernsey1, 2, Binyou Zheng1, Lee F. Siebert5, Ann Hoskin-Mott6, Michael T. Trese7, Simon N. Pimstone3, Barkur S. Shastry8, Randall T. Moon4, Michael R. Hayden3, 9, Y. Paul Goldberg3, 9
& Mark E. Samuels31
Department of Ophthalmology, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, Nova Scotia B3H 2Y9, Canada. 2
Department of Pathology, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada. 3
Xenon Genetics, Inc., Burnaby, British Columbia V5G 4W8, Canada. 4
Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, USA. 5
Department of Ophthalmology, University of Western Ontario, London, Ontario, Canada. 6
Department of Ophthalmology, QEII Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada. 7
William Beaumont Hospital, Royal Oak, Michigan, USA. 8
Department of Biological Sciences, Oakland University, Rochester, Michigan, USA. 9
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada. 10
These two authors contributed equally to the work.
Correspondence should be addressed to Michael R. Hayden mrh@cmmt.ubc.caFamilial 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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