Aims: To investigate the frequency of USH2A mutation and the clinical and genetic differences between Usher syndrome type II (USH2) and retinitis pigmentosa (RP) in a large cohort of Chinese patients.Methods: A total of 1381 patients with inherited retinal disease (IRD) were recruited. The phenotypic and genotypic information of patients with USH2A mutations was evaluated.Results: The prevalence of patients with USH2A mutations was 15.75%, which was the most frequently detected gene in this cohort of patients. Hotspot of USH2A mutations was c.8559-2A >G and c.2802T >G. Patients with USH2 had an earlier and more serious decline of visual function and damage to retina structure than did patients with RP in the first 10 years (p0.05). Missense variants had less severe consequences and were found more commonly in RP, whereas more deleterious genotypes were associated with an earlier onset of disease and were found more commonly in USH2.Conclusions: This study provides detailed clinical–genetic assessment of patients with USH2A mutations of Chinese origin, enabling precise genetic diagnoses, better management of these patients and putative therapeutic approaches.

Increasing evidence indicates that nobiletin (NOB) is a promising neuroprotective agent. Astrocyte activation plays a key role in neurodegenerative disorders. Thus, this study aims to investigate the effects of NOB on astrocyte activation and the potential mechanisms. In this study, astrocytes were exposed to hypoxia injury for 24 h to induce activation in vitro. Glial fibrillary acidic protein (GFAP) was chosen as a marker of astrocyte activation. To evaluate the effects of NOB on the migration of activated astrocytes, we used a scratch wound healing assay and Transwell migration assay. In addition, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential, Nrf2 and HO-1 were measured to investigate the mechanisms of NOB in the activation of astrocytes. We found that NOB alleviated astrocyte activation and decreased GFAP expression during hypoxia. Simultaneously, NOB alleviated the migration of astrocytes induced by hypoxia. With NOB treatment, hypoxia-induced oxidative stress was partially reversed, including reducing the production of ROS and MDA. Furthermore, NOB significantly improved the mitochondrial dysfunction in activated astrocytes. Finally, NOB promoted Nrf2 nuclear translocation and HO-1 expression in response to continuous oxidative damage. Our study indicates, for the first time, that NOB alleviates the activation of astrocytes induced by hypoxia in vitro, in part by ameliorating oxidative stress and mitochondrial dysfunction. This provides new insights into the neuroprotective effects of NOB.

Purpose: To provides the clinical and genetic characteristics of a series of Chinese patients with X‐linked juvenile retinoschisis (XLRS) through multimodal imaging and next‐generation sequencing.Methods: Thirty patients (60 eyes) from 29 unrelated families of Chinese origin with XLRS were screened using multigene panel testing, and underwent a complete clinical evaluation. All variants identified in this study and reported in the Human Gene Mutation Database were analysed.Results: Twenty‐five distinct variants in the retinoschisin gene were identified, of which eight were novel, and one was de novo. Missense mutations were the most prevalent type, and mutation hot spot was localized in the discoidin domain. The mean Snellen best‐corrected visual acuity was 0.28 ± 0.17. Of all eyes presenting with schisis, 92.86% had lamellar schisis and 62.5% had peripheral schisis. Schisis changes mostly involved inner and outer nuclear layers. X‐linked juvenile retinoschisis (XLRS) patients had a high incidence of complications, and peripheral schisis was a risk factor for it. No obvious genotype–phenotype association was observed.Conclusion: This study provides comprehensive analyses of the genetic and clinical characteristics of XLRS in a cohort of Chinese patients. The fourth de novo mutation in RS1 was identified. And we show that XLRS has a wide spectrum of clinical characteristics; hence, molecular diagnosis is crucial for its diagnosis, differential diagnosis and genetic counselling. Peripheral schisis is a risk factor for the high incidence of complications, and no clear genotype–phenotype correlations were found.

Subretinal fibrosis significantly contributes to vision loss in neovascular age‐related macular degeneration (nAMD). Epithelial‐to‐mesenchymal transition (EMT) in RPE cells is a key early step in subretinal fibrosis. While mitochondrial dysfunction in RPE is involved, the metabolic and molecular connections between EMT and mitochondria are not well understood. This study explores the role of oxoglutarate carrier (OGC; Slc25a11) on EMT and investigates the molecular mechanisms, focusing on its role in mitochondrial metabolism and GSH transport. OGC‐silenced or overexpressed ARPE‐19 cells were treated with TGF‐β2 (10 ng/mL) for 48 h. EMT markers, cell migration, mtGSH, and mitochondrial bioenergetics and signaling pathways were assessed. In vivo, subretinal fibrosis was induced in wild‐type and OGC ^+/− mice via laser photocoagulation. Fibrosis volume was measured using optical coherence tomography and immunostaining in RPE‐choroid flat mounts. OGC silencing aggravated EMT, while overexpression attenuated TGF‐β2‐induced EMT, cell proliferation, and migration. OGC knockdown significantly enhanced RPE EMT, as evidenced by upregulated expression of α‐SMA, fibronectin, collagen type I, and Slug, while E‐cadherin was downregulated. OGC overexpression improved mitochondrial bioenergetics, whereas its inhibition reduced mitochondrial respiration, which was further aggravated by co‐treatment with TGF‐β2. Loss of OGC promoted cell proliferation and migration through Slug‐mediated EMT. OGC depletion stimulated EMT via pSmad2/3 upregulation, dependent on the PI3K/AKT signaling pathway activation. In vivo studies further demonstrate that subretinal fibrosis was significantly augmented in OGC ^+/− mice via TGF‐β2‐dependent PI3K signaling. In conclusion, modulating OGC expression in RPE affects EMT and mitochondrial function, making OGC a potential therapeutic target for subretinal fibrosis in nAMD.

This study aimed to elucidate the reliability of clinical impressions based on ocular manifestations in patients suspected of heritable connective tissue disorders (HCTDs) compared to the final genetic diagnosis. Furthermore, it sought to determine the optimal diagnostic strategy for patients with HCTDs through pathogenicity analysis. Clinical characteristics of 58 patients suspected of HCTDs were analyzed to establish provisional clinical diagnoses. Subsequently, next-generation sequence and Sanger sequence was performed to obtain genetic diagnoses. Pathogenicity of identified variants was assessed through conservation analysis and the functional impact, which was predicted using three-dimensional protein structure modeling. The provisional clinical diagnosis was concordant with the molecular diagnostic result in only 21 patients. Independent of the initial clinical impression, a probable genetic diagnosis was achieved for all 58 patients following comprehensive re-analysis of next-generation sequence data, combined with pathogenicity assessment using three-dimensional protein structure and conservation analysis of suspicious positive variants. This study broadens the mutational spectrum of HCTDs with 31 novel variants. By employing innovative methodologies to delineate phenotype–genotype relationships, including the detection of potentially pathogenic variants, this work may inform future diagnostic strategies and guide comprehensive disease and organ system monitoring. Ongoing refinement and vigilant clinical oversight remain essential for patients and their families.

Familial amyloid polyneuropathy (FAP) caused by a genetic mutation in transthyretin (TTR) is an autosomal dominant hereditary disease. The retrospective, observational case series study presents the ocular clinicopathological findings of five cases carrying the TTR mutation c.401A>G (p.Tyr134Cys). Multimodal retinal imaging and electrophysiological examination, Congo red staining and immunohistochemical analysis of specimens, and genetic analyses were performed. Cases 1 and 2 were symptomatic with vitreous and retinal amyloid deposition and poor visual recovery. Case 3 had a symptomatic vitreous haze in the left eye with good postoperative visual recovery. The right eye of case 3 and the eyes of cases 4 and 5 were asymptomatic. Thicker retinal nerve fiber layer, retinal venous tortuosity with prolonged arteriovenous passage time on fluorescein angiography and retinal dysfunction detected by multifocal electroretinogram occurred even in asymptomatic eyes. Moreover, the internal limiting membrane from patients with FAP was stained positive for Congo red and transforming growth factor-β1. The results highlight the amyloid deposition of mutant TTR in the optic disc and retina, even in the asymptomatic stage. The deposited amyloid leads to increased resistance to venous return and retinal functional abnormalities. Therefore, careful follow-up of structural and functional changes in the retina is needed, even in asymptomatic patients with FAP.