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Nat Genet 2002 Oct 01;322:326-30. doi: 10.1038/ng957.
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Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.

Robitaille J , MacDonald ML , Kaykas A , Sheldahl LC , Zeisler J , Dubé MP , Zhang LH , Singaraja RR , Guernsey DL , Zheng B , Siebert LF , Hoskin-Mott A , Trese MT , Pimstone SN , Shastry BS , Moon RT , Hayden MR , Goldberg YP , Samuels ME .

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/Ca(2+) 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.

PubMed ID: 12172548
Article link: Nat Genet

Species referenced: Xenopus laevis
Genes referenced: endoul fzd4 ndp
GO keywords: retina vasculature development in camera-type eye

Disease Ontology terms: exudative vitreoretinopathy