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 (EVRI; 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.
Original language | English |
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Pages (from-to) | 326-330 |
Number of pages | 5 |
Journal | Nature Genetics |
Volume | 32 |
Issue number | 2 |
DOIs | |
Publication status | Published - Oct 1 2002 |
Bibliographical note
Funding Information: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.
ASJC Scopus Subject Areas
- Genetics
PubMed: MeSH publication types
- Case Reports
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.