Heterozygote loss-of-function variants in the LRP5 gene cause familial exudative vitreoretinopathy

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited ocular disease with clinical manifestations of aberrant retinal vasculature. We aimed to identify novel causative variants responsible for FEVR and provided evidence for the genetic counselling of FEVR.

Methods: We applied whole-exome sequencing (WES) on the genomic DNA samples from the probands and performed Sanger sequencing for variant validation. Western blot analysis and luciferase assays were performed to test the expression levels and the activity of mutant proteins.

Results: We identified one novel heterozygous nonsense variant, and three novel heterozygous frameshift variants including c.1801G>T (p.G601*), c.1965delC (p.H656Tfs*41), c.4445delC (p.S1482Cfs*17), and c.4482delC (p.P1495Rfs*4), which disabled the function of LRP5 on the Norrin/β-catenin signalling. Overexpression of variant-carrying LRP5 proteins resulted in down regulation of the protein levels of β-catenin and the Norrin/β-catenin signalling target genes c-Myc and Glut1.

Conclusion: Our study showed that four inherited LRP5 variants can cause autosomal dominant FEVR via down regulation of Norrin/β-catenin signalling and expanded the spectrum of FEVR-associated LRP5 variants.