Variable reduction in Norrin signaling activity caused by novel mutations in identified in patients with familial exudative vitreoretinopathy.

PURPOSE

To identify novel mutations in and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR).

METHODS

Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in on its biologic activity in the Norrin/β-catenin signaling pathway was analyzed with the luciferase reporter assay.

RESULTS

Four novel mutations in (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably.

CONCLUSIONS

Four novel mutations in were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.