Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4mutations (H69Y and C181R)

Abstract

Background:Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by impaired vascularization of parts of the peripheral retina. Autosomal dominant FEVR (adFEVR), a major form of FEVR and assigned to chromosome 11q13–23 (EVR1) locus, is caused by deletion mutations in the C-terminal region of the frizzled-4 (FZD4) gene. This paper describes the clinical phenotype of adFEVR in two Japanese families with two different mutations in the FZD4gene. Methods:We encountered three Japanese patients with adFEVR and studied them using mutation analysis of the FZD4gene with PCR, sequencing, and a restriction enzyme digestion. Results:Two previously unreported missense mutations, p.H69Y and p.C181R, were identified in the N-terminal extracellular region of two of the patients. This region was highly conserved among other vertebrate species and FZD family members, unlike the C-terminal region. Co-segregation analysis revealed that all affected individuals carried one of these mutations, while unaffected individuals did not. The mutations were not detected in normal individuals (n = 120). The affected individuals had mild to severe retinal abnormalities. Conclusions: FZD4mutations in either the N- or C-terminal region underlie adFEVR, which indicates that FZD4plays an important role in retinal angiogenesis. Analysis of FZD4mutations in families with adFEVR is useful for genetic counseling and for early diagnosis.