Investigative ophthalmology & visual science最新文献

{"title":"IMI-2025 Digest.","authors":"Nina Tahhan, Mark A Bullimore, Xiangui He, Lisa A Ostrin, Timothy J Gawne, Kate L Gifford, Pauline Kang, Ian Morgan, Aude Couturier, Kyoko Ohno-Matsui, Nicola S Logan, Ian Flitcroft","doi":"10.1167/iovs.66.12.27","DOIUrl":"10.1167/iovs.66.12.27","url":null,"abstract":"<p><p>As myopia research expands in scope and complexity, the International Myopia Institute (IMI) continues to provide timely, evidence-based consensus guidance through its biennial white papers and digests. The IMI 2025 Digest delivers targeted updates in areas identified for revision since the previous digest: definitions and classification of myopia, clinical management guidelines, risk factors, accommodation and binocular vision, experimental models, and onset and progression in young adults. A major focus is the evolving concept of pre-myopia, including a refined understanding of hyperopic reserve as a predictive marker, population-specific thresholds, and the distinction between risk and predictive factors. Emerging evidence supports earlier identification and targeted interventions during the pre-myopic phase to delay onset. Clinical management updates highlight that delaying onset by even 1 year may have greater lifetime benefit than multiple years of progression control. Other updates address the limited causal inference of many current risk factor studies, new molecular insights from experimental models, and evidence that a subset of young adults, particularly with high myopia, continue to progress at meaningful rates. Collectively, the IMI 2025 Digest underscores the importance of proactive, individualized myopia care, equipping clinicians with current, evidence-based guidance while supporting continued research and innovation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"27"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Characterization of the Rhesus Macaque Lens Nucleus: Similarity to Human Lens, Age Effects on Protein Solubility, and Trends in Post-Translational Modifications.","authors":"Billy L Hayden, Owen Kelley, Keith Zientek, Ashok P Reddy, Phillip A Wilmarth, Rachel Munds, Michael J Montague, Melween I Martinez, Gadi Wollstein, James P Higham, Arturo O Barron Arrambide, John Danias, Amanda D Melin, Larry L David, Jeremy A Whitson","doi":"10.1167/iovs.66.12.28","DOIUrl":"10.1167/iovs.66.12.28","url":null,"abstract":"<p><strong>Purpose: </strong>Proteomes of lens nuclei from young (4 years old) and old (15-16 years old) rhesus macaques (Macaca mulatta) were analyzed to determine similarity of the proteomic profile to that of human lenses, age-related differences in protein solubility, and association of various post-translational modifications with age and protein solubility.</p><p><strong>Methods: </strong>Lens core proteins were separated into water-soluble and water-insoluble fractions using aqueous buffer and centrifugation. The water-insoluble fraction was solubilized using sodium dodecyl sulfate (SDS). Proteins were processed using S-trap columns, and peptide digests were analyzed using high-resolution, label-free data-dependent acquisition (DDA) proteomics. Open modification searches were performed using MSFragger to identify possible post-translational modifications (PTMs). The number of modified peptide tandem mass spectra confidently assigned to samples by age or solubility were compared to find PTMs with statistically significant count differences.</p><p><strong>Results: </strong>The overall proteomic profile of rhesus macaque lenses was very similar to human lenses, consisting of 80.2% crystallins, 1.1% beaded filament proteins, and 18.7% other proteins. The crystallin fraction consisted of 27% alpha crystallins, 67.6% beta/gamma crystallins, and 5.4% taxon-specific psi crystallin. Glycolytic enzymes, beta/gamma crystallins, and a few glutathione-related enzymes were found to have age-related shifts to the water-insoluble fraction. There were significant differences in deamidation, dioxidation, carbamylation, carboxymethylation, and trioxidation based on age and/or solubility of proteins.</p><p><strong>Conclusions: </strong>These data indicate a high level of conformity between rhesus macaque and human lens proteomes, and a few key differences. We identified several age-related differences in protein solubility and PTM that may contribute to lens pathology.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"28"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Pigmentation Heritage and Susceptibility to Experimentally Induced Myopia: Crossbreeding Insights From Albino and Pigmented Guinea Pigs.","authors":"Liqin Jiang, Yee Shan Dan, William E Myles, Sherlyn H Y Seah, James H Z Koh, Myo Thu Khine, Leopold Schmetterer, Veluchamy A Barathi, Quan V Hoang","doi":"10.1167/iovs.66.12.47","DOIUrl":"10.1167/iovs.66.12.47","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate how pigmentation heritage affects susceptibility to form deprivation myopia (FDM) through crossbreeding myopia-susceptible albino and myopia-resistant pigmented guinea pigs (GPs).</p><p><strong>Methods: </strong>Ninety GPs (albino: n = 29, pigmented: n = 29, F1 crossbred: n = 32) were studied. Eye parameters were measured using retinoscopy and A-scan ultrasound. Scotopic electroretinograms were recorded by full-field electroretinography in 36 naive GPs at 1 and 5 weeks of age. Monocular form deprivation (FD) was applied from 1 to 5 weeks of age in 27 GPs, with 27 littermates as controls. The retina, choroid, and sclera were imaged using optical coherence tomography. From control GPs at 5 weeks, scleral melanin was assessed histologically; choroidal melanin and tyrosinase activity in the choroid and sclera were quantified biochemically.</p><p><strong>Results: </strong>Crossbreds had a pigmented appearance, and choroidal thickness (ChT, 100 ± 19 µm) was thicker than in albino GPs (69 ± 12 µm, P < 0.001) but thinner than in pigmented GPs (124 ± 19 µm, P = 0.004). Choroidal melanin content and tyrosinase activity followed similar patterns and were significantly different (one-way ANOVA): highest in pigmented GPs, intermediate in crossbreds, and undetectable in albinos. Albinos exhibited the largest a-wave amplitudes across the intensity-response functions among the three breeds. Crossbreds displayed a monotonic b-wave intensity-response function, similar to but with higher amplitudes than pigmented GPs, whereas albinos showed a bell-shaped response pattern before the second rise. FD induced significant myopic shift and axial elongation in albinos (spherical equivalent [SE]: -7.83 ± 4.74 D, P = 0.001; axial length [AL]: 0.20 ± 0.14 mm, P = 0.003) and crossbreds (SE: -5.42 ± 2.90 D, P < 0.001; AL: 0.17 ± 0.09 mm, P = 0.001). Pigmented GPs showed a mild myopic shift (-2.08 ± 1.93 D, P = 0.01) with no significant AL changes (0.03 ± 0.08 mm, P = 0.357). FDM severity differed across breeds (SE: P = 0.006, AL: P = 0.004); thicker baseline ChT was associated with less FDM in crossbreds (P = 0.027) and reduced axial elongation in albinos (P = 0.004); retinal and scleral thicknesses were nonpredictive.</p><p><strong>Conclusions: </strong>Crossbreeding improved retinal function and choroidal morphology, while preserving susceptibility to FDM, suggesting a partial restoration of myopia-inducible mechanisms inherited from the albino lineage. These findings support the value of the crossbred model for investigating retinal and choroidal regulation in myopia.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"47"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exon Skipping Therapy Restores Ciliary Function in USH2A-Related Retinal Degeneration.","authors":"Wuyi Li, Yamei Li, Yunyu Zhou, Yue Liu, Huixin Liu, Xing Wei, Zixi Sun, Xiaoxu Han, Xuan Zou, Hui Li, Ruifang Sui","doi":"10.1167/iovs.66.12.46","DOIUrl":"10.1167/iovs.66.12.46","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to evaluate the exon-skipping efficacy and safety of an antisense oligonucleotide (AON) targeting USH2A exon 13 across multiple models, including the Rb1 cell line, humanized USH2A-e13 transgenic mice, and patient-derived retinal organoids. Additionally, we investigated the pathogenic mechanisms of USH2A variants and the therapeutic effects of exon skipping on photoreceptor cilia structure and function.</p><p><strong>Methods: </strong>Bioinformatic tools were used to design AONs targeting USH2A exon 13, and their exon-skipping efficiency was assessed at both RNA and protein levels in Rb1 cells. A humanized USH2A-e13 transgenic mouse model was generated via gene editing and received intravitreal AON injections. Retinal distribution, exon-skipping efficiency, and toxicity were evaluated through fundus fluorescence imaging, immunofluorescence staining, droplet digital PCR (ddPCR), Western blot (WB), apoptosis assays, and electroretinography (ERG). Patient-derived induced pluripotent stem cells (iPSCs) were differentiated into retinal organoids and analyzed using transcriptomic profiling, immunofluorescence, ddPCR, WB, apoptosis assays, and transmission electron microscopy (TEM).</p><p><strong>Results: </strong>PUMCH-E13 effectively induced exon 13 skipping in the Rb1 cell line, USH2A-e13 mice (44.44% ± 1.61% reduction), and patient-derived retinal organoids (16.4% ± 4.1% reduction). No significant adverse effects were observed through apoptosis assays or ERG. Additionally, treatment with PUMCH-E13 resulted in the restoration of GPR98 and PDZD7 expression within the USH2 complex, alongside the reorganization of microtubule structures in the photoreceptor cilia.</p><p><strong>Conclusions: </strong>PUMCH-E13 effectively induces exon 13 skipping in USH2A with low toxicity. Additionally, PUMCH-E13 can promote the restoration of photoreceptor cilia structure in patient-derived retinal organoids, revealing its potential therapeutic mechanism.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"46"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing Long-Chain 3-Hydroxy-Acyl-CoA Dehydrogenase Deficiency (LCHADD) Chorioretinopathy Using OCT and OCTA.","authors":"Xiaohui Hua, Tristan T Hormel, Jie Wang, Dongseok Choi, Mark E Pennesi, Melanie B Gillingham, Yali Jia","doi":"10.1167/iovs.66.12.57","DOIUrl":"10.1167/iovs.66.12.57","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize structural and microvascular alterations in chorioretinopathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) using optical coherence tomography (OCT) and OCT angiography (OCTA).</p><p><strong>Methods: </strong>Thirty-six eyes from 19 patients with LCHADD were evaluated and categorized into six stages of increasing severity. Avanti and Solix OCTA devices were used to scan acquire 3 × 3-mm macular scans of the eyes. The thicknesses of the inner retina, outer retina, and choroid were measured from OCT scans. Vessel density (VD) and nonperfusion area (NPA) were calculated from en face projection-resolved OCTA in four slabs: the superficial vascular complex, intermediate capillary plexus, deep capillary plexus (DCP), and choriocapillaris (CC). The correlations (Spearman's rank) between these structural and angiographic metrics and traditional clinical metrics (the LCHADD severity, best-corrected visual acuity [BCVA], and plasma acylcarnitines) were investigated.</p><p><strong>Results: </strong>Pronounced thinning in the outer retina and choroid was observed, along with marked VD loss and increased NPA in the DCP and CC at severe stages. The outer retinal and choroidal thicknesses correlated with all traditional clinical metrics, VD/NPA in the DCP and CC were significantly correlated with the LCHADD severity and BCVA, and only VD/NPA in the CC were associated with plasma acylcarnitines.</p><p><strong>Conclusions: </strong>Combined OCT/OCTA imaging enables visualization and quantification of structural and microvascular alterations in the chorioretinal slabs at different stages of LCHADD. The pathology of LCHADD impacts the deeper retinal plexuses more than the inner layers. OCT and OCTA parameters may improve understanding of the pathological changes in LCHADD chorioretinopathy and aid in monitoring disease progression.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"57"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Independent Effects of Axial Length and Intraocular Pressure on the Highly Myopic Optic Nerve Head.","authors":"Maverick Wenhao Wong, Crystal Chong, Swati Sharma, Lee Ching Phang, Samantha Lor, Quan V Hoang, Michael Girard, Ching-Yu Cheng, Leopold Schmetterer, Jost B Jonas, Hongli Yang, Ya Xing Wang, Jin Wook Jeoung, Rachel S Chong","doi":"10.1167/iovs.66.12.49","DOIUrl":"10.1167/iovs.66.12.49","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to investigate associations among intraocular pressure (IOP), axial length (AXL), and optic nerve head (ONH) characteristics in highly myopic eyes.</p><p><strong>Methods: </strong>This retrospective cross-sectional study included highly myopic eyes with a refractive error of ≤-6.0 diopters (D) or an AXL of ≥26 mm, without glaucomatous optic neuropathy. Using IOP profiles, obtained retrospectively over a 5-year period, we assessed maximum, median, and range of IOP readings. We performed cross-sectional measurements of morphometric ONH parameters on fundus photographs and optical coherence tomographic (OCT) images.</p><p><strong>Results: </strong>The study included 201 eyes (134 individuals) with a mean AXL of 27.6 ± 1.4 mm and a mean maximum IOP of 16.6 ± 3.7 millimeters of mercury (mm Hg; median = 14.9 ± 2.5 mm Hg, range = 3.14 ± 3.13 mm Hg obtained in 5.25 ± 2.76 measurements). Longer AXL was associated (multivariable analysis) with higher disc ovality (β = 0.05, P < 0.001), longer disc-fovea distance (β = 0.22, P < 0.001), shallower lamina cribrosa depth (β = -20.5, P = 0.02), and thicker ganglion cell layer and retinal nerve fiber layer in the temporal/inferotemporal sectors (all P < 0.05) with adjustments for age and gender. Higher mean maximum IOP readings were linked to deeper lamina cribrosa depth (β = 6.03, P = 0.006) and reduced disc rotation angle (β = -0.31, P = 0.04); higher mean median IOP was associated with smaller Bruch's membrane opening area (β = -0.06, P = 0.02). AXL was inversely associated with mean median IOP (β = -0.19, P = 0.02).</p><p><strong>Conclusions: </strong>Higher IOP and longer AXL are associated with distinct structural changes of the ONH in highly myopic eyes, particularly involving the lamina cribrosa. Elevated IOP but not AXL was associated with ONH features characteristic of glaucoma.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"49"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid and Cholesterol Peroxidation Leads to α-Crystallin Membrane Aggregation and Cataract Formation.","authors":"Nawal K Khadka, Preston Hazen, Oluwaseyi Akinola, Xinzhu Pu, Laxman Mainali","doi":"10.1167/iovs.66.12.8","DOIUrl":"10.1167/iovs.66.12.8","url":null,"abstract":"<p><strong>Purpose: </strong>The significant lens chaperone protein α-crystallin (αABc), comprised of αA-crystallin (αAc) and αB-crystallin (αBc) subunits, is found to form membrane-bound aggregates with age and cataract formation. However, the molecular basis for such aggregate formation is still unclear. Our research primarily aims to elucidate the effect of lipids (phospholipids and sphingolipids) and cholesterol (Chol) peroxidation on the aggregation of αAc, αBc, and αABc to bovine lens nuclear membrane (NM).</p><p><strong>Methods: </strong>Lipid and Chol peroxidation was induced by a photosensitized peroxidation reaction, and topographical images of NM and oxidized-NM (Ox-NM) with and without αAc, αBc, or αABc were obtained using atomic force microscopy (AFM).</p><p><strong>Results: </strong>The percentage of membrane area occupied (PMAO) by αAc, αBc, or αABc aggregates on NMs was significantly smaller without lipid and Chol peroxidation. However, with NM lipid and Chol peroxidation, the PMAO of αAc, αBc, or αABc aggregates on the Ox-NM was significantly more extensive, and PMAO increased with an increase in lipid and Chol peroxidation. Large-size aggregates of αAc, αBc, or αABc on Ox-NM with the depressed central region for αAc and αABc aggregates on Ox-NM were observed to a greater extent with increased lipid and Chol peroxidation.</p><p><strong>Conclusions: </strong>Lipid and Chol peroxidation induce membrane defects on NM, followed by extensive aggregation of αAc, αBc, and αABc on Ox-NM, suggests that lipid and Chol peroxidation promotes the aggregation of αAc, αBc, and αABc to Ox-NM, and the formation of such large aggregates likely promotes increased light scattering and cataract formation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"8"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Function Associations of Choroidal Thickness With Retinal Sensitivity in Myopia.","authors":"Syna Sreng, Joey Chung, Angeline Toh, Yvonne Ng Bei Zhen, Leila Sara Eppenberger, Jacqueline Chua, Quan V Hoang, Rachel S Chong, Anna C S Tan, Leopold Schmetterer, Marcus Ang, Damon Wong","doi":"10.1167/iovs.66.12.21","DOIUrl":"10.1167/iovs.66.12.21","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to investigate the focal relationship between choroidal thickness and retinal sensitivity in myopic eyes.</p><p><strong>Methods: </strong>Participants underwent swept-source optical coherence tomography (SS-OCT) imaging and microperimetry testing. Choroidal thicknesses were obtained by segmenting the SS-OCT scans using a deep-learning approach. Retinal sensitivity was measured at 33 locations using scotopic microperimetry, and corresponding focal choroidal thickness at these locations were computed. Focal structure-function associations between retinal sensitivity and choroidal thickness across 15 retinal eccentricities were evaluated, and adjusted for retinal thickness, signal strength, age, axial length, and gender.</p><p><strong>Results: </strong>The analysis included 280 eyes from 155 participants (mean age = 25.8 ± 3.0 years) with myopia with a mean axial length of 26.56 ± 0.99 mm and refractive error of -6.87 ± 2.05 diopters (D). Mean retinal sensitivity was 27.68 ± 1.28 decibels (dB). Mean choroid thickness was 217.85 ± 66.66 µm, with choroidal thickness in the nasal quadrant significantly thinner than in the other quadrants. Choroidal thicknesses were correlated with retinal sensitivity in 14 of 15 retinal regions, including the global eccentricity zone (r = 0.261, P < 0.001). Significant associations were similarly found with retinal thickness (r = 0.305, P < 0.001), age (r = 0.182, P < 0.05), and axial length (r = -0.402, P < 0.001). Focal structure-function models further substantiated these relationships, demonstrating a significant effect size (β = 0.78, 95% confidence interval [CI] = 0.39-1.16, P < 0.001) after adjusting for retinal thickness and other demographic factors.</p><p><strong>Conclusions: </strong>Significant associations between choroidal thickness measurements and microperimetry were observed in a cross-sectional cohort of myopic eyes, suggesting a structure-function relationship with retinal sensitivity at the choroid. Further studies will be required to evaluate this in other cohorts and in progression.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"21"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Mouse Model of Granular Corneal Dystrophy Type II Reveals Impaired Autophagy and Recapitulates Human Pathogenesis.","authors":"Yanze Yu, Zhe Zhang, Zimeng Zhai, Bingqing Sun, Dongmei Yang, Zhanying Wang, Qinghong Lin, Xingtao Zhou, Jing Zhao","doi":"10.1167/iovs.66.12.7","DOIUrl":"10.1167/iovs.66.12.7","url":null,"abstract":"<p><strong>Purpose: </strong>To develop and characterize a novel mouse model of granular corneal dystrophy type II (GCD2) using CRISPR/Cas9 technology and explore the underlying pathogenesis of transforming growth factor-beta-induced protein (TGFBIp) aggregation.</p><p><strong>Methods: </strong>CRISPR/Cas9 technology was employed to introduce the R124H mutation in the TGFBI gene of mice. Genomic sequencing and polymerase chain reaction confirmed the mutation. Phenotypic characteristics were evaluated through slit-lamp examination, optical coherence tomography, histological analysis, electron microscopy, and immunofluorescence, comparing wild-type (WT), heterozygous (HE), and homozygous (HO) mice. Transcriptome sequencing was conducted to identify the pathogenesis of GCD2. The findings were further validated through western blotting and transmission electron microscopy.</p><p><strong>Results: </strong>The R124H mutation in TGFBI was successfully introduced, with breadcrumb-like deposits observed in the corneas of mutant mice, with HO mice displaying more severe phenotypes than HE mice. TGFBIp levels were elevated in HE and HO mice (both P < 0.001). Histological and electron microscopy analyses revealed abnormal collagen arrangement and TGFBIp deposits in the corneal stroma of the HE and HO mice. Transcriptome analysis indicated that the TGFBI-R124H mutation was associated with impaired autophagy, endocytosis, and extracellular matrix signaling. Additional experiments confirmed autophagy-related markers LC3 and SQSTM1 were upregulated in the corneas of mutant mice, accompanied by increased autophagosome formation in corneal keratocytes, indicating impaired autophagy flux in HE and HO mice.</p><p><strong>Conclusions: </strong>We established a GCD2 mouse model caused by the R124H mutation using CRISPR/Cas9, providing a reliable platform for understanding pathogenesis for GCD2.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"7"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel BEST1 Variant Characterization in a Large French Cohort in Light of Updated Bestrophin-1 Structure-Function Correlation.","authors":"Joan Bitan, Anaïs F Poncet, Claire Lecigne, Aurore Devos, Isabelle Meunier, Xavier Zanlonghi, Olivier Grunewald, Vasily Smirnov, Claire-Marie Dhaenens","doi":"10.1167/iovs.66.12.4","DOIUrl":"10.1167/iovs.66.12.4","url":null,"abstract":"<p><strong>Purpose: </strong>To update knowledge on bestrophin-1 structure and function with the aim of assessing the pathogenicity of variants reported in the Leiden Open Variation Database (LOVD) and in a large French cohort of bestrophinopathies.</p><p><strong>Methods: </strong>All unique variants reported in the latest version (October 2024) of the BEST1-LOVD database were uploaded and curated. We described all BEST1 variants identified in French patients analyzed at Lille University Hospital, between 2008 and 2024. A comprehensive analysis of each variant was performed based on in silico tools (at DNA, RNA, and protein levels), as well as a literature review providing clinical data and functional assays. All of these data were used to classify the variant pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) criteria.</p><p><strong>Results: </strong>We detailed 488 variants from the LOVD. Among 450 French patients, we identified 150 different variants, 40 of which were novel. We classified only eight variants as variants of unknown significance, four of which were already in the LOVD. We identified specific recurrent variants in the French population: p.(Gly26Asp), p.(Val90Met), p.(Val137Met), and p.(Ile230del), the last of which was present in 17 patients (3.8%). All new variants cause changes in chemical interactions within the protein and are associated with clinical pictures of bestrophinopathy.</p><p><strong>Conclusions: </strong>The study and comparison of these two large cohorts highlight variants specific to the French population, as well as differences in protein distribution, which are undoubtedly influenced by several population-specific factors. Through multiple in silico analyses, we were able to reclassify 93.3% of variants as likely pathogenic or pathogenic, thereby strengthening clinical diagnoses.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"4"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}