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.

Intravitreous (i.v.t.) injection is increasingly being incorporated into the management of ocular diseases. While only fomivirsen sodium (Vitravene) is currently approved by the Food and Drug Administration as an i.v.t. injection, the number of approved i.v.t. injections indications is anticipated to grow on the basis of promising results from ongoing clinical studies. Despite the potential benefits that may be derived from intraocular injections of different agents, no guidelines have been published previously for i.v.t. injection. The purpose of this document is to identify specific strategies for the delivery of i.v.t. injection that may reduce risks and improve outcomes. Consensus was sought among a panel of investigators, surgeons experienced with this technique, and industry representatives. Objective evidence was sought for all guidelines, but consensus was accepted where evidence remains incomplete. In the absence of either evidence or consensus, the current manuscript identifies outstanding issues in need of further investigation. It is anticipated that more complete guidelines will evolve over time, potentially altering some of the guidelines included here, based on new applications of i.v.t. injection, additional clinical experience, and results of clinical trials.

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