Investigative ophthalmology & visual science最新文献

{"title":"The Transcription Factor Islet-1 Regulates Diabetes-Induced Inner Blood-Retinal Barrier Disruption.","authors":"Nan Wang, Fei Yao, Wenji Xu, Tianxu Feng, Zhenyu Li, Quyan Zhang, Wanpeng Wang, Xueyong Zhang, Wenbo Lei, Guoli Zheng, Yao Xu, Die Liu, Yiming Zhu, Xiaobo Xia, Siqi Xiong","doi":"10.1167/iovs.66.13.8","DOIUrl":"https://doi.org/10.1167/iovs.66.13.8","url":null,"abstract":"<p><strong>Purpose: </strong>The transcription factor Islet-1 (Insulin gene enhancer protein Isl-1) has been implicated in diabetic retinal neovascularization, but its role in inner blood-retinal barrier (iBRB) dysfunction in diabetic retinopathy remains unclear. This study aimed to elucidate the mechanisms by which Islet-1 drives iBRB disruption under diabetic conditions by integrating analyses of clinical samples from patients with diabetic retinopathy, in vivo studies in diabetic mouse models, and in vitro experiments using hyperglycemia-exposed human retinal microvascular endothelial cells.</p><p><strong>Methods: </strong>The expression profile of Islet-1 in diabetic patients and experimental diabetic models were investigated by immunofluorescence staining, Western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Through the modulation of Islet-1 expression, we evaluated its impact on iBRB integrity under diabetic conditions and explored the molecular pathways involved in iBRB disruption.</p><p><strong>Results: </strong>Our findings demonstrated that elevated Islet-1 expression correlates with the progression of diabetic retinopathy and the breakdown of the iBRB. Mechanistically, Islet-1 upregulation led to increased vascular endothelial growth factor A (VEGFA) expression and decreased levels of key tight junction proteins Occludin and Zonula occludens-1 (ZO-1) in retinal vascular endothelial cells.</p><p><strong>Conclusions: </strong>Our results establish Islet-1 as a critical regulator of iBRB disruption in diabetic retinopathy and suggest that targeting Islet-1 overexpression may represent a novel therapeutic approach to mitigate iBRB dysfunction and its associated retinal pathologies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"8"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging Affects Lipid Homeostasis in Lacrimal Glands by Upregulating Lipogenesis and Changing Its Specificity.","authors":"Seher Yuksel, Prashant Kumar, Sydney E Krenz, Kaitlin K Scholand, Zhiyuan Yu, Anastasiia Ivanova, Helen P Makarenkova, Sarah F Hamm-Alvarez, Igor A Butovich, Cintia S de Paiva","doi":"10.1167/iovs.66.13.1","DOIUrl":"https://doi.org/10.1167/iovs.66.13.1","url":null,"abstract":"<p><strong>Purpose: </strong>The lacrimal gland (LG) develops age-related alterations. This study investigated the lipid content of the accumulated secretions within the murine aged LG.</p><p><strong>Methods: </strong>C57BL/6J animals of different ages (3 months, 12 months, and 20-26 months) were used. Published data of bulk RNA sequencing of aged LGs were used to investigate lipid pathways. Exorbital LGs were excised for histology or PCR. Histologic sections were stained with standard histochemical stains or immunostained using anti-adiponectin, anti-perilipin 2 antibodies, and BODIPY dye. LG lipidomes were investigated using unbiased, untargeted high-resolution liquid chromatography/mass spectrometry (LC/MS), and the data were processed using unbiased, untargeted principal component and orthogonal projections to latent structure discriminant analyses.</p><p><strong>Results: </strong>Analyses of aged LGs revealed distinct changes in their state: immune infiltration without and with large dilated epithelial ducts. Sudan black and Oil Red O staining of cystic LG sections demonstrated lipid accumulation within the dilated epithelial ducts, accompanied by lymphocytic infiltration around dilated ductal structures. Bulk RNA sequencing of glands indicated upregulated transcription of genes associated with lipid metabolism, fatty acid synthesis, and lipid droplet formation. Adiponectin protein expression was restricted to ducts. Immunoreactivity to perilipin 2 and BODIPY was only observed in aged epithelial ducts. Moreover, lipidomic LC/MS analysis revealed a significant increase in the total lipid content in aged LGs compared to young LGs, with a pronounced accumulation in the neutral lipid fraction, particularly triglycerides.</p><p><strong>Conclusions: </strong>The changes in LG lipidomes of aging mice indicate a considerable age-related shift in the specificity and efficacy of lipogenesis in LG.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"1"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgene-Induced Chromosomal Rearrangement With Aberrant Human Vascular Endothelial Growth Factor at the Optic Fissure Leads to Uveal Coloboma in Mice.","authors":"Yuhong Anna Wang, Ramakrishna P Alur, Vijay Kalaskar, Aman George, Elangovan Boobalan, David M McGaughey, Felix I Onojafe, Amalia Dutra, Evgenia Pak, James W Thomas, Lijin Dong, Marcus Fruttiger, Sandra Pieke-Dahl, Bin Guan, Peter F Hitchcock, Brian P Brooks","doi":"10.1167/iovs.66.13.7","DOIUrl":"https://doi.org/10.1167/iovs.66.13.7","url":null,"abstract":"<p><strong>Purpose: </strong>The pathogenesis of uveal coloboma, a potentially blinding congenital ocular malformation, is incompletely understood. We characterize a novel mouse model of coloboma, Retinal and Iris Coloboma (RICO).</p><p><strong>Methods: </strong>Transgenic mice were created by insertion of a human vascular endothelial growth factor-165 (hVEGF) gene driven by a neuron-specific enolase promoter. Mice were examined clinically and histologically, and the insertion site was characterized by fluorescence in situ hybridization and genomic sequencing. Gene expression changes were assessed with RNA sequencing, immunofluorescence, and in situ hybridization.</p><p><strong>Results: </strong>RICO mice are viable in the homozygous state and exhibit fully penetrant autosomal semidominant coloboma. Coloboma is associated with persistence of periocular mesenchyme in the optic fissure, likely contingent on a specific, transgene insertion-induced genomic rearrangement on chromosome 13 that drives aberrant hVEGF expression. RICO eye cups exhibit altered expression of genes in the vicinity of the insertion site, where deletions of the human homologous locus were found in coloboma patients. RNA sequencing demonstrates changes in multiple coloboma-associated genes.</p><p><strong>Conclusions: </strong>RICO represents a useful model for studying the pathogenesis of human coloboma.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"7"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Most Resistant and Vulnerable Retinal Ganglion Cell Subtypes in a Chronic Model of Glaucoma in Rat.","authors":"Noelia Ruzafa, Xandra Pereiro, Laura Prieto-López, Aritz Urcola, Arantxa Acera, Elena Vecino","doi":"10.1167/iovs.66.13.5","DOIUrl":"https://doi.org/10.1167/iovs.66.13.5","url":null,"abstract":"<p><strong>Purpose: </strong>Retinal ganglion cells (RGCs) transmit visual information to the brain and are selectively affected in glaucoma, a neurodegenerative disease caused by increased intraocular pressure (IOP) leading to vision loss. Not all RGC subtypes are equally vulnerable; thus, this study aimed to comprehensively analyze the differential loss of RGC subtypes using a rat model of chronic glaucoma.</p><p><strong>Methods: </strong>A chronic glaucoma model was established by cauterizing three episcleral veins in rat eyes. IOP was measured using an applanation tonometer, and after 40 days animals were euthanized. Whole-mount retinas were immunostained. RGCs were labeled with anti-RNA-binding protein with multiple splicing (RBPMS; marks 100% of RGCs) and co-labeled with subtype-specific antibodies: CART, melanopsin (OPN4), Foxp2, Islet1/2, SPP1, and Tbr2. RGC loss and subtype distribution were quantified as percentages of RBPMS-positive cells in different retinal regions.</p><p><strong>Results: </strong>In glaucomatous eyes, RGC survival decreased in the retinal periphery, with 65.44% in the dorsal-nasal and 76.03% in the ventral-temporal regions. CART-positive RGCs dropped from 32.9% ± 5.15% to 20.26% ± 2.64% (dorsal-nasal) and from 33.07% ± 4.09% to 22.65% ± 2.65% (ventral-temporal), indicating higher vulnerability. In contrast, OPN4-positive RGCs increased from 3.27% ± 1.34% to 6.99% ± 2.31% (dorsal-nasal), suggesting greater intrinsically photosensitive RGC (ipRGC) resilience. Percentages of SPP1-, Foxp2-, Islet1/2-, and Tbr2-positive RGCs remained unchanged, suggesting proportional loss to total RGC reduction.</p><p><strong>Conclusions: </strong>RGC subtypes showed differing susceptibilities to IOP, with OPN4-positive RGCs (ipRGCs) being more resistant and CART-positive RGCs (ON-OFF direction-selective ganglion cells [ooDSGCs]) highly vulnerable. This highlights the need to study ooDSGC degeneration and explore targeted neuroprotection. Future research should develop therapies to protect, regenerate, or replace ooDSGCs.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"5"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-Driven Histone Modifications Govern Gene Regulation for Mature Eye Lens Formation.","authors":"Lisa Brennan, Joshua Disatham, Marc Kantorow","doi":"10.1167/iovs.66.13.2","DOIUrl":"https://doi.org/10.1167/iovs.66.13.2","url":null,"abstract":"<p><strong>Purpose: </strong>Evidence suggests that the hypoxic environment of the lens regulates the expression of genes required for lens formation and function. Here, we tested the hypothesis that hypoxia regulates these genes through the induction of specific histone modifications.</p><p><strong>Methods: </strong>Global levels of hypoxia-induced histone modifications were determined in cultured day 13 chick lenses exposed to 1% oxygen. The genome-wide localizations of H3K27ac and H3K4me3 were identified by cleavage under target and release using nuclease analysis and mapped to within 5 kb of the transcriptional start sites of genes activated or repressed by hypoxia identified by RNA sequencing. The requirement for these histone modifications for hypoxia-induced gene expression was determined using inhibitors of histone writers and erasers.</p><p><strong>Results: </strong>The levels of activating modifications H3K4me3, H3K9ac, H3K14ac, and H3K27ac in hypoxia-treated lenses increased, whereas levels of repressive modifications H3K9me3 and H3K27me3 remained unchanged. Hypoxia-specific H3K4me3 and/or H3K27ac regions were detected within 5 kb of the transcriptional start sites of more than 900 fiber cell genes with increased expression upon hypoxia exposure and 350 genes with decreased expression. The inhibition of histone writers and erasers resulted in altered levels of key fiber cell genes upon hypoxia exposure.</p><p><strong>Conclusions: </strong>These results provide evidence that hypoxia-induced histone modifications regulate the genes required for mature lens formation and provide a framework for understanding the role of hypoxia-specific histone modifications in the regulation of genes in more complex tissues.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"2"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choroidal Vascular Fingerprints From Indocyanine Green Angiography Unveil Chorioretinal Disease State.","authors":"Ruoyu Chen, Ziwei Zhao, Mayinuer Yusufu, Xianwen Shang, Mingguang He, Danli Shi","doi":"10.1167/iovs.66.13.3","DOIUrl":"https://doi.org/10.1167/iovs.66.13.3","url":null,"abstract":"<p><strong>Purpose: </strong>To develop an annotation-efficient deep learning algorithm for extracting multi-dimensional features of choroidal vasculature on indocyanine green angiography (ICGA) images via a human-in-the-loop (HITL) strategy and explore their relationship with multiple chorioretinal diseases.</p><p><strong>Methods: </strong>The segmentation model was trained on a multi-source dataset that included both 55° ICGA and 200° ultra-widefield ICGA (UWF-ICGA) images, using a HITL strategy. Choroidal vascular fingerprints were generated from the segmentation maps, quantifying diameter, density, complexity, tortuosity, and branching angle. Reliability was assessed using intraclass correlation coefficients (ICC), and normal ranges for each measurement were estimated. The study retrospectively included 243 eyes diagnosed with central serous chorioretinopathy (CSC), polypoidal choroidal vasculopathy (PCV), or pathological myopia (PM), as well as 151 normal control eyes, to investigate their association with choroidal vascular fingerprints. Multivariable logistic regression models were used for the analysis.</p><p><strong>Results: </strong>The model achieved high segmentation accuracy, with the area under the receiver operating characteristic curve being 0.975 (95% confidence interval [CI, 0.967-0.983) for 55° view ICGA images and 0.937 (95% CI, 0.914-0.960) for UWF-ICGA images. Twenty-six, 28, and 29 multidimensional measurements were significantly associated with CSC, PCV, and PM, respectively (P value < 0.05). The ICC values for 74 choroidal vascular measurements ranged from 0.71 (95% CI, 0.51-0.84) to 0.97 (95% CI, 0.95-0.99).</p><p><strong>Conclusions: </strong>This pioneering study revealed choroidal vascular fingerprints and validated their associations with various chorioretinal diseases. These findings pave the way for future exploration of the pathological mechanisms underlying these conditions.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"3"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lego Self-Assembly Model of Zebrafish RGB Cone Pentamer Formation: Unique Role of Crumbs2b in Cone Coalescence via Planar Orientational Cell Adhesions.","authors":"Jong-Su Park, Chuanyu Guo, Xiangyun Wei","doi":"10.1167/iovs.66.13.6","DOIUrl":"https://doi.org/10.1167/iovs.66.13.6","url":null,"abstract":"<p><strong>Purpose: </strong>Vertebrate retinal photoreceptors are non-randomly patterned into planar mosaics. In zebrafish, red, green, and blue (RGB) cones coalesce into linear mirror-symmetric pentamers (G-R-B-R-G) by unknown mechanisms. Here, we investigate the role of the Crumbs2b (Crb2b) polarity protein in pentamer formation and maintenance.</p><p><strong>Methods: </strong>The crb2bsa21178 null mutation was used to study the Crb2b functions. Confocal microscopy was used to examine tissue morphologies and protein distribution.</p><p><strong>Results: </strong>Crb2b, which localizes anisotropically in the planar and apicobasal axes in RGB cones, is required for RGB cone pentamer formation. Crb2b deficiency causes RGB cones to form a new bead-thread configuration, a finding that reveals additional new insights: Crb2b is required for parallel alignment of RGB cone interfaces; the pentamer patterning defect induced by loss of Crb2b is accompanied by planar patterning defect in rods, ultraviolet cones, and Müller cell apical processes; among RGB cones, G-R and R-B are preferred coalescences, which do not require Crb2b; RGB cones display self-avoidance, in which Crb2b does not play a major role; cone survival does not require Crb2b; and, without affecting the overall retinal apicobasal polarization, Crb2b deficiency causes excessive rods and thickening of the inner plexiform layer.</p><p><strong>Conclusions: </strong>We propose a Lego self-assembly model as a theory to explain the formation and maintenance of RGB cone pentamers. This model has six elements, among which Crb2b may regulate the geographical distribution and strengths of planar orientational cell adhesions (pOCA). This model exemplifies how distinct OCAs can promote self-assembly of various tissue architectures.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"6"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TYROSINASE-Deficient Human Retinal Pigment Epithelium Exhibits Melanosome Maturation Defects.","authors":"Aman George, Tyler Pfister, Charles DeYoung, Ruchi Sharma, Mones Abu-Asab, Jizhong Zou, Kapil Bharti, Brian P Brooks","doi":"10.1167/iovs.66.13.4","DOIUrl":"https://doi.org/10.1167/iovs.66.13.4","url":null,"abstract":"<p><strong>Purpose: </strong>Oculocutaneous albinism type 1A (OCA1A) is a rare recessive genetic condition caused by mutations in TYROSINASE (TYR) that results in pigmentation defects of the skin, hair and eyes. This study was performed to understand melanosome biogenesis and maturation defects in an OCA1A in vitro model using retinal pigment epithelium (RPE) derived from TYR knockout human induced pluripotent stem cells (iPSC).</p><p><strong>Methods: </strong>CRISPR-Cas9 was used to knockout the TYR gene in iPSC to generate an isogenic pair. A developmentally guided protocol was used to differentiate the isogenic iPSC pair towards RPE monolayer tissue. Monolayer organization, melanosome formation and maturation were studied using electron microscopy. Loss of TYR protein was studied using Western blot and immuno-fluorescence staining. RPE cellular morphology and junction integrity was studied using immunofluorescence staining and transepithelial resistance measurements.</p><p><strong>Result: </strong>An isogenic pair comprising of untargeted control and TYR knockout iPSC were successfully differentiated towards RPE monolayer tissue with polygonal cell morphology. TYR knockout RPE exhibited significantly reduced TYR protein, increased presence of immature pre-melanosomes and a complete lack of mature melanosomes. We observed abnormal junctional localization of β-catenin staining pattern, as has been reported previously for albino mouse RPE- and OCA1A patient-derived RPE.</p><p><strong>Conclusions: </strong>Differentiation of TYR-deficient iPSC toward RPE displayed pigmentation defects and absence of mature melanosomes, whereas melanosome biogenesis was not affected, because pre-melanosomes were still observed. These observations were also similar to what was observed in OCA1A patient-derived RPE monolayer tissue, independently confirming the validity of these previous findings.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"4"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum in: Isolated Mitochondrial Transplantation as a Novel Treatment for Corneal Chemical Burns.","authors":"","doi":"10.1167/iovs.66.12.14","DOIUrl":"10.1167/iovs.66.12.14","url":null,"abstract":"","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"14"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12429678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000556","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":"Genome-Wide Insights Into the Genes and Pathways Shaping Human Foveal Development: Redefining the Genetic Landscape of Foveal Hypoplasia.","authors":"Callum Hunt, Ha-Jun Yoon, Alvin Lirio, Kayesha Coley, Jun Wang, Nick Shrine, Jianming Shao, Gail D E Maconachie, Zhanhan Tu, Jonathan H Zippin, Pirro G Hysi, Christopher J Hammond, Omar A Mahroo, Mariya Moosajee, Michel Michaelides, Andrew R Webster, Ala Moshiri, Rui Chen, Martin D Tobin, Chiara Batini, Mervyn G Thomas","doi":"10.1167/iovs.66.12.22","DOIUrl":"10.1167/iovs.66.12.22","url":null,"abstract":"<p><strong>Purpose: </strong>To define the genetic architecture of foveal morphology and explore its relevance to foveal hypoplasia (FH), a hallmark of developmental macular disorders.</p><p><strong>Methods: </strong>We applied deep-learning algorithms to quantify foveal pit depth from central optical coherence tomography (OCT) B-scans in 61,269 UK Biobank participants. A genome-wide association study (GWAS) was conducted using REGENIE, adjusting for age, sex, height, and ancestry. Rare coding variants (frequency <1%) were analyzed in an exome-wide rare-variant association study (RVAS). Candidate genes were prioritized using integrative mapping; pathway, cross-ancestry, and genetic-correlation analyses were exploratory.</p><p><strong>Results: </strong>GWAS identified 126 sentinel variants, including 47 novel associations. Integrative mapping prioritized 129 putative causal genes, with 64 not previously implicated in foveal biology. Enriched pathways included retinoic acid metabolism (e.g., CYP26A1), photoreceptor differentiation (e.g., VSX2), extracellular matrix organization, and pigmentation. RVAS identified missense variants in ACTN3 and ESYT3 (P < 5 × 10-⁹) associated with FH features. Polygenic scores were predictive across African and South Asian ancestries. Overlap was observed with monogenic FH genes (TYR, OCA2, PAX6, AHR) and with genes underlying systemic diseases (COL11A1, KIF11, TUBB4B, PHYH). Re-examination of OCTs in affected individuals confirmed FH in select cases, including those with recurrent TUBB4B p.(Arg390Trp) variants.</p><p><strong>Conclusions: </strong>This is the first GWAS of human foveal morphology. Our findings redefine the genetic and biological framework underlying normal foveal development and foveal hypoplasia (FH). By linking common variation to rare monogenic disease, we establish a continuum model of FH with implications for future mechanistic and clinical investigation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 12","pages":"22"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023383","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}