ERCC8基因移码突变导致圆锥角膜合并先天性白内障的致病机制研究

Abstract

Purpose:The purpose of this study was to identify a new candidate gene for keratoconus and congenital cataracts and further investigate its underlying pathogenic mechanisms.Methods:This study, using a Chinese family with keratoconus and congenital cataracts, 262 patients with sporadic keratoconus, and 20 patients with sporadic congenital cataract as subjects, used clinical and genetic analysis and in vitro cell experiments to detect genetic mutations and further investigate the underlying pathogenic mechanisms.Results:We found that a novel frameshift mutation ofERCC8(NM_000082.3: c.394-398del, p. L132Nfs*6) is responsible for familial keratoconus with congenital cataracts. This mutation showed co-segregation with the phenotype in the family. This was revealed in another patient with sporadic keratoconus, absent in the 210 unrelated health controls, and considered to be “disease-causing.”ERCC8was expressed both in the cornea and lens. Through an in vitro cell experiment, we further demonstrated that the mutant proteins ofERCC8were degraded and could lead to an insufficient dose of the ERCC8 protein. An insufficient dose reduced the DNA damage repair ability of human corneal fibroblast (HTK) and lens epithelial cells (HLEC) treated with hydrogen peroxide, leading to both cells showing higher DNA damage levels. In addition, it decreased cell viability, resulting in decreased collagen expression in HTK and increased apoptosis in HLEC via aberrant activation of the unfolded protein response. All these results suggested thatERCC8plays an important role in the normal function of corneal stromal and lens epithelial cells.Conclusions:Our study showed thatERCC8is a new gene associated with keratoconus and congenital cataracts.Chinese Abstract