Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract.

High myopia is a severe visual impairment which can increase the risk of retinal degeneration, subretinal hemorrhage, choroidal neovascularization, cataract and retinal detachment. We recruited an autosomal-recessive high myopia family, with affected subjects who also present early-onset cataract, retinal degeneration and other complications. Using targeted capturing and whole exome sequencing, we identified a homozygous non-sense mutation in the LEPREL1 gene which causes premature termination of the translation at the fifth amino acid (c.13C>T; p.Q5X), co-segregating with the phenotypes. LEPREL1 encodes a proline hydroxylase called prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The results show that LEPREL1 plays an important role in eye development and homozygous loss-of-function mutation of this gene can cause severely high myopia and early-onset cataract. Our study also strongly suggests that the disruption of collagen modification is one of the pathogenic mechanisms of high myopia and cataract.