Familial exudative vitreoretinopathy (FEVR) is an inheritable retinal vascular disease, which often leads to severe vision loss and blindness in children. However, reported mutations can only account for 50-60% of patients with FEVR. The purpose of this study was to identify novel frizzled class receptor 4 () and Norrin cystine knot growth factor NDP () mutations in a cohort of Indian patients with FEVR by whole-exome sequencing. We performed data filtering and bioinformatic analyses. Two novel heterozygous mutations in gene were identified, each in two different families: c.1499_1500del [p.500_500del] and c.G296C [p.C99S]. One novel mutation in in another family was identified: c.A256G [p.K86E]. All mutations affected conserved amino acid residues and were absent in 1000 control individuals. To assess the effect of these mutations on the biological activity of the protein, we introduced each mutation into cDNA by the site-directed mutagenesis techniques. A Norrin/beta-catenin pathway-based luciferase reporter assay revealed that the c.1499_1500del failed to activate the luciferase reporter; in contrast, compared with the wild-type FZD4 protein, the, c.G296C [p.C99S] mutation exhibited increased luciferase reporter activity. Our study found two novel mutations, with opposite effects regarding functional expression levels in Indian patients with FEVR and expands on the mutational spectrum of in Indian FEVR patients.
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