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Abstract Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are characterized by distinct genetic causes and molecular mechanisms that can lead to varying degrees of visual impairment. The discovery of pathogenic variants in numerous genes associated with these conditions has deepened our understanding of the molecular pathways that influence both vision and disease manifestation and may ultimately lead to novel therapeutic approaches. Over the past 18 years, our DNA diagnostics unit has been performing genetic testing on patients suspected of having IRD or ION, using state-of-the-art mutation detection technologies that are continuously updated. This report presents a retrospective analysis of genetic data from 6237 IRD and 780 ION patients. Out of these, 3054 IRD patients (49.0%) and 211 ION patients (27.1%) received a definitive molecular diagnosis, with disease-causing variants identified in 139 different genes. The genes most implicated in disease pathologies are ABCA4, accounting for 23.8% of all IRD/ION index cases, followed by BEST1 (7.8%), USH2A (6.2%), PRPH2 (5.7%), RPGR (5.6%), RS1 (5.5%), OPA1 (4.3%), and RHO (3.1%). Our study has compiled the most extensive dataset in combined IRD/ION diagnostics to date and offers valuable insights into the frequencies of mutant alleles and the efficiency of mutation detection in various inherited retinal conditions.

Abstract The trabecular meshwork (TM) is crucial for regulating intraocular pressure (IOP), and its dysfunction significantly contributes to glaucoma, a leading cause of vision loss and blindness worldwide. Although rodents are commonly used as animal models in glaucoma research, the applicability of these findings to humans is limited due to the insufficient understanding of murine TM. This study aimed to compare primary human TM (hTM) and murine TM (mTM) cells in vitro to enhance the robustness and translatability of murine glaucoma models. In this in vitro study, we compared primary hTM and mTM cells under simulated physiological and pathological conditions by exposing both cell types to the glucocorticoid dexamethasone (DEX) and Transforming Growth Factor β (TGFB2), both of which are critical in the pathogenesis of several ophthalmological diseases, including glaucoma. Phagocytic properties were assessed using microbeads. Cells were analyzed through immunocytochemistry (ICC) and Western blot (WB) to evaluate the expression of extracellular matrix (ECM) components, such as Fibronectin 1 (FN1) and Collagen IV (COL IV). Filamentous-Actin (F-Act) staining was used to analyze cross-linked actin network (CLAN) formation. Additionally, we evaluated cytoskeletal components, including Vimentin (VIM), Myocilin (MYOC), and Actin-alpha-2 (ACTA2). Our results demonstrated significant similarities between human and murine TM cells in basic morphology, phagocytic properties, and ECM and cytoskeletal component expression under both homeostatic and pathological conditions in vitro. Both human and murine TM cells exhibited epithelial-to-mesenchymal transition (EMT) after exposure to DEX or TGFB2, with comparable CLAN formation observed in both species. However, there were significant differences in FN1 and MYOC induction between human and murine TM cells. Additionally, MYOC expression in hTM cells depended on fibronectin coating. Our study suggests that murine glaucoma models are potentially translatable to human TM. The observed similarities in ECM and cytoskeletal component expression and the comparable EMT response and CLAN formation support the utility of murine models in glaucoma research. The differences in FN1 and MYOC expression between hTM and mTM warrant further investigation due to their potential impact on TM properties. Overall, this study provides valuable insights into the species-specific characteristics of TM and highlights opportunities to refine murine models for better relevance to human glaucoma.