Abstract
Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease characterized by defects in the development of retinal vessels. However, known genetic mutations can only explain approximately 50% of FEVR patients. To assess the mutation frequency of Frizzled 4 (FZD4) in Chinese patients, we analysed patients with FEVR from 61 families from China to identify mutations in FZD4 and to study the effects of identified mutations on FZD4 function. All coding exons and adjacent intronic regions of FZD4 were amplified by polymerase chain reaction and subjected to Sanger sequencing analysis. Three mutations in the FZD4 gene were identified in these families. Of these, two were novel mutations: p.E134* and p.T503fs. Both mutations involve highly conserved residues and were not present in 800 normal individuals. Each of these two novel FZD4 mutations was introduced into wild-type FZD4 cDNA by site-directed mutagenesis. Wild-type and mutant FZD4 DNAs were introduced into HEK293 cells to analyse the function of FZD4 in Norrin-dependent activation of the Norrin/β-catenin pathway using luciferase reporter assays. Both the p.E134* and p.T503fs mutants failed to induce luciferase reporter activity in response to Norrin. Our study identified two novel FZD4 mutations in Chinese patients with FEVR.
Highlights
IntroductionMutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD), can lead to FEVR condition[13]
TSPAN12 and NDP genes are components of the Norrin/β-catenin signalling pathway
We screened for mutations in the FZD4 gene in 61 Chinese families with an autosomal dominant form of FEVR and found two novel mutations
Summary
Mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD), can lead to FEVR condition[13]. Previous studies suggested that known FEVR mutations explain approximately 40–60% of the autosomal dominant forms of FEVR cases in different populations[7,8,14,15,16,17,18]. We screened for mutations in the FZD4 gene in 61 Chinese families with an autosomal dominant form of FEVR and found two novel mutations. We demonstrate that these two mutations in FZD4 lead to the loss of FZD4 activity
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