Molecular Vision最新文献

Purpose: To characterize the distribution of reticular fibers in the human sclera and explore their potential role in the pathogenesis of pathologic myopia and posterior staphyloma.

Methods: Central sagittal sections of 13 globes (6 right eyes and 7 left eyes) were obtained from 12 East Asian cadavers aged 38-94 years (mean age: 74.9 years). Three scleral regions were examined: the pars plana, 3:00-3:30 clock-hour position, and 5:00-5:30 clock-hour position. Specimens were fixed in 10% formalin and stained with silver nitrate. ImageJ software was used for image processing and quantification of fiber density.

Results: Reticular fiber density exhibited considerable inter- and intraindividual variability. The average densities at the pars plana, 3:00-3:30, and 5:00-5:30 were 31.07%, 26.10%, and 22.70%, respectively. Density ranges were 23.46%-58.51% (pars plana), 19.18%-43.07% (3:00-3:30), and 13.48%-50.95% (5:00-5:30). In 10 eyes, the pars plana showed the highest density, followed by 3:00-3:30 and then 5:00-5:30. Two eyes had the lowest density at 3:00-3:30, while one eye exhibited the highest density in this region.

Conclusions: Reticular fiber density in the sclera exhibits considerable interindividual variability. Our findings suggest that regions of structural vulnerability within the sclera may extend beyond the posterior pole, potentially offering new insights into the pathogenesis of posterior staphyloma. A reduction in reticular fiber density may be implicated in the progression of pathologic myopia and the development of posterior staphylomas, although further investigation is warranted to substantiate this association.

Purpose: Diabetic retinopathy (DR) is of the most prevalent complications among diabetic patients. The potential role of interleukin 15 (IL-15) in modulating immune cell function and angiogenesis has drawn considerable attention. Nevertheless, the precise mechanism through which IL-15 operates in DR remains elusive.

Methods: The GSE185011 and GSE221521 data sets were harnessed to screen for upregulated genes in the blood and peripheral blood mononuclear cells (PBMCs) of patients with DR. The GSE236333 and GSE179568 data sets were used to identify upregulated genes in retinal tissues. In the clinical investigation, IL-15 was detected in T and B lymphocytes, as well as in monocytes/macrophages within the PBMCs of patients. Human retinal microvascular endothelial cells and human umbilical vein endothelial cells were either cocultured with the monocyte/macrophage cell line THP-1 under high-glucose (HG) conditions or treated with IL-15.

Results: Among the three cell types in PBMCs, monocytes/macrophages exhibited the most substantial upregulation of IL-15 under HG conditions. In vitro, IL-15 secreted by THP-1 cells augmented the STAT5 in human retinal microvascular endothelial cells and human umbilical vein endothelial cells, thereby enhancing their angiogenic potential. Inhibition of STAT5 expression counteracted the proangiogenic effect of IL-15 on endothelial cells and diminished the expression of epithelial cell adhesion molecule 1 (EFNA1). After the knockdown of nuclear receptor coactivator 2 (NCOA2), the binding affinity of STAT5 to the EFNA1 gene promoter was significantly attenuated, and the influence of IL-15 on EFNA1 expression and angiogenesis was markedly reduced. Intriguingly, knockdown of either EFNA1 or NCOA2 led to a concurrent decrease in the expression of both genes in endothelial cells, suggesting a positive feedback regulatory loop between them.

Conclusions: IL-15 secreted by monocytes/macrophages activates STAT5, which in turn induces a positive feedback regulation of the EFNA1/NCOA2 axis, ultimately promoting retinal angiogenesis under HG conditions.

Purpose: Genetic polymorphisms in syntrophin beta-1 (SNTB1) have been implicated in altering protein function or expression, potentially influencing ocular growth regulation. Genome-wide association studies (GWASs) suggest that specific SNTB1 variants may correlate with high myopia susceptibility across diverse populations. However, findings remain inconsistent, highlighting the need for further investigation into population-specific genetic effects and underlying mechanisms.

Methods: Accordingly, the PubMed and Wanfang databases were searched for articles published until June 1, 2025, using the keywords SNTB1 or syntrophin beta-1, polymorphism, and myopia or shortsightedness. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to examine the association. The SNTB1 rs6469937 polymorphism genotypes were identified with the TaqMan assay.

Results: Four related studies were conducted to better understand the association between SNTB1 gene polymorphisms and high myopia risk. The SNTB1 rs4455882 site was associated with a decreased overall high myopia risk (e.g., G vs. A; OR = 0.815; 95% CI, 0.688-0.984; p _{heterogeneity} = 0.465; p = 0.017). Similar trends were detected in the rs4395927 site (e.g., T vs. C; OR = 0.791; 95% CI, 0.670-0.935; p _{heterogeneity} = 0.199; p = 0.006) and rs6469937 site (e.g., A vs. G; OR = 0.811; 95% CI, 0.697-0.944; p _{heterogeneity} = 0.030; p = 0.007). Furthermore, high myopia patients carrying the SNTB1 rs6469937 AA+AG genotypes exhibited pronounced increases in serum levels of SNTB1 compared to the GG genotype (p < 0.01) but showed an opposite trend compared to genotype-matched normal controls (p < 0.05).

Conclusions: The current study suggested that the SNTB1 rs4455882, rs4395927, and rs6469937 polymorphisms may be potential influencing factors of high myopia. Furthermore, the rs6469937 polymorphism may offer value as a candidate variant requiring validation that can aid in the early identification and prognostic evaluation of high myopia.

Purpose: Primate eyes feature a physiologic accommodative system identical to that of humans. Nonetheless, their biometric changes before and after cycloplegia have not been investigated. In this study, we aimed to evaluate the characteristics of pseudomyopia and explore factors associated with cycloplegic changes in young cynomolgus macaques.

Methods: Refractive and biometric measurements were performed on both eyes before and after cycloplegia in 88 cynomolgus macaques aged 3-6 years without ocular diseases. Pseudomyopia was defined as autorefraction-estimated noncycloplegic spherical equivalent (NSE) < -0.50 D and cycloplegic spherical equivalent (CSE) ≥ -0.50 D. Linear mixed models were established to identify factors associated with cycloplegic differences.

Results: After excluding low-quality ophthalmic data, 149 eyes were included in the final analysis. The median NSE was -0.38 (interquartile range: -1.50, 0.25) D and the median CSE was 0.13 (-0.50, 0.90) D, exhibiting a robust Pearson's correlation coefficient of 0.89 (95% confidence interval: 0.78-0.92). Pseudomyopia was observed in 35 of the 149 eyes, with a greater hyperopic shift (median, 1.42 D) compared to that in non-myopic and true-myopic eyes (median, 0.50 D for both, p<0.001). Pseudomyopic eyes demonstrated active accommodation before cycloplegia and exhibited biometric changes after cycloplegia akin to those in true-myopic eyes. Under cycloplegia, non-myopic and pseudomyopic eyes exhibited similar biometric measurements. A greater hyperopic shift correlated with a higher hyperopic NSE and greater reductions in lens thickness.

Conclusions: The use of 1% cyclopentolate yielded discernible alterations in refractive and biometric parameters in 3- to 6-year-old cynomolgus macaques. Notably, compared with non-myopia and true myopia, pseudomyopia exhibited associations and discrepancies in accommodative status. These findings underscore the importance of investigating the role of the lens in animal models employed in myopia research.

Purpose: To identify causative genetic variants and associated clinical phenotypes in patients of a tertiary referral center in Brazil with suspected retinitis pigmentosa (RP).

Methods: RP diagnosis was established based on predefined clinical criteria. The patients underwent detailed ophthalmologic assessments and multimodal retinal imaging. Genomic DNA was analyzed using a next-generation sequencing (NGS) panel targeting 238 genes associated with inherited retinal diseases.

Results: Among 55 patients, the genetic diagnostic yield was 71% (39/55), with 13 novel variants identified. The most frequently implicated genes were RHO, RPGR, and USH2A, accounting for approximately 50% of genetically diagnosed cases. Fundus autofluorescence revealed patchy hypoautofluorescence surrounding the vascular arcades as the most frequent finding. On spectral-domain optical coherence tomography, the pattern of ellipsoid zone presentation in the central macula was significantly correlated with best-corrected visual acuity (p<0.001).

Conclusions: This study delineates the genetic and phenotypic spectrum of RP in a tertiary Brazilian referral center, highlighting the utility of NGS for molecular diagnosis and clinical management.

Purpose: To elucidate the molecular mechanisms of retinopathy of prematurity (ROP) and identify potential drug targets for its treatment based on bioinformatics analysis.

Methods: We obtained gene expression profiles from data sets GSE123945 and GSE135844 in the Gene Expression Omnibus database. Differential expression analysis was performed on GSE135844 to identify differentially expressed genes (DEGs). Ferroptosis-related genes were retrieved from FerrDb, and Venn diagrams were used to identify overlapping genes between DEGs and ferroptosis-related genes. Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis, were conducted to explore the biological roles of these genes. Protein-protein interaction networks were constructed using the STRING database, and hub genes were identified using Cytoscape. Potential drug targets were screened using the Drug-Gene Interaction Database.

Results: We identified 23 DEGs associated with ferroptosis in ROP. These genes were significantly enriched in biological processes such as angiogenesis, vasculature development, and wound healing. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the PI3K-Akt signaling pathway plays a central role in ROP pathogenesis. Gene set enrichment analysis identified the defense response as the most significantly enriched gene set. Hub genes, including HMOX1, ALB, and JUN, were identified through protein-protein interaction network analysis. Potential drugs targeting these hub genes, such as stannsoporfin, recombinant neurotrophic factors, zinc chloride, and irisolidone, were identified using the Drug-Gene Interaction Database.

Conclusions: Our study demonstrates the utility of bioinformatics approaches in identifying ferroptosis-related genes and potential drug targets for ROP. The findings provide a foundation for further experimental validation and the development of novel therapeutic strategies for ROP.

Purpose: Inherited retinal dystrophies (IRDs) encompass a genetically and clinically heterogeneous group of disorders, with over 300 genes currently implicated. Early and precise genetic diagnosis is critical for advancing targeted gene therapies and personalized treatment strategies. This study aims to investigate genetic findings in IRDs using whole-exome sequencing (WES) in a cohort of affected individuals.

Methods: WES was performed on 34 unrelated probands diagnosed with diverse IRD subtypes. Variant analysis focused on identifying clinically relevant variants consistent with the patients' phenotypes and inheritance patterns, emphasizing novel and rare variants.

Results: Clinically relevant variants consistent with the patients' phenotypes and inheritance patterns were identified in 24 cases. Among these, four variants were novel: RP2 c.181_182del, CYP4V2 c.377T>G, RPGR c.1414G>A, and RPE65 c.267C>G. Additionally, we identified a patient with isolated IRD carrying a homozygous IFT81 c.1969C>T (p.Gln657Ter) variant, a gene typically associated with syndromic phenotypes. Furthermore, we reported a relatively rare presentation of ARSG-related Usher syndrome in a patient harboring a homozygous ARSG c.263G>T (p.Arg88Leu) alteration.

Conclusions: This study underscores the diagnostic power of WES in IRDs, revealing novel variants and supporting its integration into clinical practice to enhance early diagnosis and enable precision medicine.

Background: Proteostasis impairment is central to cellular dysfunction in protein aggregation disorders such as Alzheimer disease, Parkinson disease, and age-related macular degeneration. Pseudoexfoliation (PEX), a systemic age-related disorder and a leading cause of secondary glaucoma, is increasingly recognized as a protein aggregation disease. It is characterized by the deposition of pseudoexfoliative material (PEXM) in ocular tissues, leading to elevated intraocular pressure and optic neuropathy.

Objective: This review synthesizes current evidence on the role of proteostasis failure in PEX pathogenesis, with a focus on molecular mechanisms, stress response pathways, and potential therapeutic interventions.

Methods: We conducted a comprehensive literature review of studies examining proteostasis mechanisms in PEX. Emphasis was placed on cellular pathways regulating protein synthesis, folding, and degradation, including the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy, as well as environmental and aging-related triggers of proteotoxic stress.

Results: Evidence indicates that chronic proteotoxic stress, arising from aging, oxidative damage, and environmental influences, disrupts the proteostasis network (PN). Dysregulation of ER stress signaling, cytosolic stress responses, and protein degradation pathways contributes to the accumulation of misfolded proteins and extracellular matrix deposits in ocular tissues. These molecular alterations underlie disease onset and progression in PEX syndrome (PEXS) and PEX glaucoma (PEXG).

Conclusions: Proteostasis dysfunction plays a pivotal role in PEX pathogenesis by promoting protein misfolding, aggregation, and extracellular deposition. Targeting the proteostasis network, through modulation of stress responses and enhancement of degradation pathways, represents a promising therapeutic strategy for PEXS and PEXG.

Purpose: Achromatopsia (ACHM) is a cone dysfunction syndrome associated with low color vision, photophobia, and congenital nystagmus. Pathogenic variants in the CNGA3 and CNGB3 genes are the most common causes of ACHM. Identifying the underlying genetic etiology in patients with clinical findings of ACHM is critical to establishing the diagnosis and selecting targets for gene therapies. This study utilizes the inherited retinal disease (IRD) database at the University of Minnesota (UMN) to understand clinical features of achromatopsia, potential diagnostic methods, and genetic variability at one large academic institution.

Methods: This retrospective cohort study examined patients with a genetically confirmed diagnosis of ACHM evaluated at the UMN/M Health IRD clinic between May 2015 and August 2022. Data were collected through UMN's electronic health record system and included information on demographics, history of ocular illness, visual acuity, and diagnostic exam results, such as electroretinogram, fundus autofluorescence, and optical coherence tomography (OCT) imaging. Genetic testing was performed using next-generation sequencing panels of varying sizes, and variants were interpreted according to American College of Medical Genetics guidelines.

Results: A total of 21 patients with a genetically confirmed ACHM were included in the study. Most patients were female (67%) and white (76%). The cohort included one pair of twin siblings and one group of three siblings. The median age of genetic testing conducted was 12 years (interquartile range, 12-20 years). One-third of patients had nyctalopia. All patients experienced difficulties with color vision, 20 of 21 (95.2%) had photosensitivity, and 18 of 21 patients reported congenital nystagmus. Diagnostic imaging showed most patients with a normal scotopic response and absent photopic response on electroretinogram, macular hyperfluorescence on fundus autofluorescence, and normal optical coherence tomography imaging.

Conclusion: This study contributes to an understanding of the phenotypes and distribution of genetic variants associated with achromatopsia at a single academic institution in the state of Minnesota, particularly those involving the CNGA3 and CNGB3 genes. Future research could explore the prevalence of these variants in larger cohorts to enhance clinical management and treatment strategies for patients with achromatopsia.

Purpose: Scotopic vision impairment as an early event is found in diabetic retinopathy. However, the underlying mechanisms behind hyperglycemia-induced scotopic vision impairment remain unclear. This study aims to identify that Grm6 is associated with glutamate accumulation-induced scotopic vision impairment under hyperglycemia.

Methods: In this study, diabetic mice with impaired scotopic vision were induced by streptozotocin, and the retinal electrical activity was evaluated using electroretinography. Label-free quantitative proteomic analysis was used to identify differentially expressed proteins in the retinas of diabetic mice. A retinal transcriptome-wide association analysis and correlation screening were performed in BXD mice strains to explore the potential genes associated with hyperglycemia. Gene function enrichment analysis was used to evaluate gene function and to construct the correlation network.

Results: In total, 151 proteins were significantly altered in the retina of diabetic mice. Among these 151 candidates, 22 genes presented a significant correlation with blood glucose level (p<0.05), which were enriched in alanine, aspartate, and glutamate metabolism (p=0.003). Moreover, the glutamate catabolism-related genes Slc1a2, Gad1, and Glud1 were significantly negatively correlated with blood glucose at the transcript and proteome levels, which led to glutamate accumulation under hyperglycemia. Among eight types of metabotropic glutamate receptors, Grm6 had the most significant correlation with blood glucose level (R=-0.5291, p=0.0003). Moreover, Grm6 expression was significantly decreased at both the mRNA and protein levels in the diabetic retina. Gene coexpression network analysis further identified that Grm6 was correlated with Rgs9, suggesting that hyperglycemia may impair scotopic vision via the phototransduction pathway.

Conclusions: Our study confirms that Grm6 is associated with scotopic vision impairment induced by glutamate accumulation in diabetic mice and provides an efficient strategy for exploring critical biomarkers and pathways through a combination of proteomics and transcriptome-wide association analysis.