Mutations in LRP5 or FZD4 underlie the common FEVR locus on chromosome 11q13

Abstract

Abstract: : Purpose: FZD4 was recently identified as the mutated gene causing familial exudative vitreoretinopathy (FEVR) at the EVR1 locus on chromosome 11q. We identified a large family with proven linkage to the original EVR1 locus (lod score 5.5) but without mutations in FZD4. The purpose of this study was to identify the mutated gene in this family. Methods: PCR products were generated from genomic DNA with primers designed to amplify the coding and flanking intronic sequences of candidate genes. The PCR products were screened for mutations by single strand conformational polymorphism–heteroduplex analysis (SSCP–HA) and by direct sequencing. Results: We identified a candidate gene in the region, low–density lipoprotein receptor–related protein 5 (LRP5). Screening of this gene in the proven EVR1 linked family identified the splice donor mutation c4488+2t→g. Screening of LRP5 in a further 32 FEVR patients identified five more mutations: K1374fsX1549, R1270fsX1438, T173M, Y1168H and C1361G. None of these mutations were present in 180 control individuals. Conclusions: We have identified FEVR causing mutations in LRP5, a second gene at the original EVR1 locus. LRP5, like FZD4, encodes a receptor for the Wnt signalling pathway, therefore further underlining the significance of this pathway in the vascularization of the eye.

Keywords: retina • gene mapping • neovascularization