Insufficient Dose of ERCC8 Protein Caused by a Frameshift Mutation Is Associated With Keratoconus With Congenital Cataracts

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 of ERCC8 (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.” ERCC8 was expressed both in the cornea and lens. Through an in vitro cell experiment, we further demonstrated that the mutant proteins of ERCC8 were 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 that ERCC8 plays an important role in the normal function of corneal stromal and lens epithelial cells. Conclusions Our study showed that ERCC8 is a new gene associated with keratoconus and congenital cataracts. Chinese Abstract

Type II Acute Macular Neuroretinopathy Secondary to Malaria

“…A study carried out by Sarraf et al in 2012 showed that AMN represented an ischaemic phenomenon and can be categorized in two distinct types based on the site of ischaemia in relation to the OPL [ 16 ]. With the advent of OCT-A, more insight was gained into the pathophysiology behind the two entities with hypotheses suggesting that the two diseases may be related in view of similar microvascular changes detected on imaging [ 1 , 17 ]. Type I AMN is characterized by hyperreflectivity in the inner nuclear layer (INL) on OCT whilst type II AMN, as depicted in this case report, is associated with hyperreflectivity in the ONL with the INL-OPL junction being the anatomical cut-off, suggesting that the deep capillary plexus could be the main target of the ischaemic event [ 1 , 17 ].…”

“…With the advent of OCT-A, more insight was gained into the pathophysiology behind the two entities with hypotheses suggesting that the two diseases may be related in view of similar microvascular changes detected on imaging [ 1 , 17 ]. Type I AMN is characterized by hyperreflectivity in the inner nuclear layer (INL) on OCT whilst type II AMN, as depicted in this case report, is associated with hyperreflectivity in the ONL with the INL-OPL junction being the anatomical cut-off, suggesting that the deep capillary plexus could be the main target of the ischaemic event [ 1 , 17 ]. The absence of capillary cross-sections at the INL/OPL junction and the presence of a draining venule crossing the INL appear to be more indicative of a type II lesion [ 1 ].…”

“…Type II AMN is an ischaemic event which occurs at the level of the deep capillary plexus [ 1 ]. Symptoms are generally limited to central and paracentral scotomata, and fundal examination may only reveal small hypopigmented wedge-shaped lesions within the macular area, given that there is no associated retinopathy [ 2 ].…”

Mitochondrial DNA heteroplasmy analysis in keratoconus patients from China

“…It is also one of the most frequent causes of corneal transplantation ( Sarezky et al, 2017 ). Although the exact cause of KC is still unclear in most patients, the genetic, environmental, and behavioral factors were reported to be associated with its pathogenesis ( Ferrari and Rama, 2020 ; Hao et al, 2022 ; Santodomingo-Rubido et al, 2022 ). Recently, several studies have reported that oxidative stress plays an important role in the development of KC ( Navel et al, 2021 ; Vallabh et al, 2017 ), and mitochondria have been implicated in the pathogenesis of KC due to its crucial role in oxidative stress ( Roy et al, 2019 ).…”

Association of Novel Loci With Keratoconus Susceptibility in a Chinese Genome-Wide Association Study

“…Several candidate genes or variants associated with KC have subsequently been identified. [11][12][13] However, some genes or variants exhibited different associations in different populations, indicating genetic heterogeneity in KC.…”