The following publications are available for download in PDF format. These documents may be viewed with Adobe Acrobat Reader. To download this free program, please click here.

Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative
Vitreoretinopathy Locus on Chromosome 11q
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor–related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.
(Read Full Article)

Vascular Development in the Retina and Inner Ear: Control by Norrin and Frizzled-4, a High-Affinity Ligand-Receptor Pair
Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.
(Read Full Article)

Spectrum and Frequency of FZD4 Mutations in Familial Exudative Vitreoretinopathy
Mutations in the frizzled-4 gene (FZD4) have recently been associated with autosomal dominant familial exudative vitreoretinopathy (FEVR) in families linking to the EVR1 locus on the long arm of chromosome 11. The purpose of this study was to screen FZD4 in a panel of 40 patients with FEVR to identify the types and location of mutations and to calculate what proportion of this heterogeneous condition is attributable to FZD4 mutations.
(Read Full Article)

Novel Mutations in FZD4 with Familial Exudative Vitreoretinopathy
Incomplete normal retinal angiogenesis is the hallmarks of a group of retinal vascular diseases including retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR). The primary pathological process in ROP and FEVR is believed to be a premature arrest of retinal angiogenesis/vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina (van Nouhuys 1991). This failure to vascularize the peripheral retina is the unifying feature seen in all affected individuals, but by itself usually causes no clinical symptoms.
(Read Full Article)