Molecular Vision[JOURNAL]
Sun
200 papers
A potential novel role of the R36P mutation in CRYGD in congenial cataract.
Tan C, Yu X, Chen J … +2 more , Sun X, Wang L
Mol Vis · 2024 · PMID 39563676
PURPOSE: Congenital cataract is an important cause of visual impairment in childhood. Our previous study reported that the c.110G>C (p.R36P) mutation in the γD-crystallin gene (CRYGD) was associated with congenital catar...
PURPOSE: Congenital cataract is an important cause of visual impairment in childhood. Our previous study reported that the c.110G>C (p.R36P) mutation in the γD-crystallin gene (CRYGD) was associated with congenital cataract in a Chinese family. This study aimed to investigate the potential underlying mechanism through which the p.R36P mutation leads to congenital cataract. METHODS: Plasmids encoding wide-type human γD-crystallin and the mutant R36P γD-crystallin were transfected into HEK293T and SRA01/04 cells. Protein expression levels, including total, soluble, and insoluble fractions, were quantified by Western blotting. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA expression of other crystallin genes. Cell viability and apoptosis were evaluated using the CCK-8 assay and flow cytometry, respectively. RESULTS: The total protein, especially the soluble fraction, was significantly reduced in the R36P mutant, while the insoluble part remained unaffected. The decrease of soluble R36P γD-crystallin could not be rescued by the proteinase inhibitor MG132. The mRNA expression of the R36P mutation was lower, but other crystallin RNAs were unchanged. Cell viability was slightly decreased (11%, p<0.05), and cell apoptosis was not significantly increased (12%, p=0.31). CONCLUSIONS: The significant decrease in soluble R36P γD-crystallin may represent a novel mechanism underlying congenital cataract caused by CRYGD gene mutation.
Erratum: A method for gene knockdown in the retina using a lipid-based carrier.
Mol Vis · 2024 · PMID 39563675
Abstract loading — click title to view on PubMed.
Toll-like receptor-4 expression and oxidative stress in ocular rosacea.
Yesilirmak N, Bukan N, Kurt B … +6 more , Fatsa T, Yuzbasıoglu S, Zhao M, Hosbul T, Bourges JL, Behar-Cohen F
Mol Vis · 2024 · PMID 39563674
PURPOSE: To investigate systemic and ocular toll-like receptor (TLR)-4 expression and its association with oxidative stress markers in ocular rosacea (OR). METHODS: This prospective study included 40 patients with rosace...
PURPOSE: To investigate systemic and ocular toll-like receptor (TLR)-4 expression and its association with oxidative stress markers in ocular rosacea (OR). METHODS: This prospective study included 40 patients with rosacea with ocular involvement and 20 healthy volunteers. Tear break-up time (TBUT), Schirmer test, meibomoscore, and ocular surface disease index (OSDI) scores were estimated for all participants. TLR-4 expression in conjunctival epithelium and peripheral blood mononuclear cells was quantified using real-time polymerase chain reaction (RT-PCR). In the tears and serum samples of all participants, antioxidant status (TAS), total oxidant status (TOS), and arylesterase (ARE) activation levels were measured using a fully automated spectrophotometric method, and the oxidative stress index (OSI) was calculated. RESULTS: TLR-4 expression levels and oxidative stress status (TOS and OSI values) were significantly higher ( < 0.01), and antioxidant status (TAS and ARE values) were significantly lower ( < 0.01) in both ocular and blood samples of patients with OR compared with those in controls. A significant positive correlation was found between the ocular and blood values in all parameters ( < 0.05). According to the clinical associations of these results, we found negative correlations between TLR-4, OSI, and TBUT and between TLR-4 and Schirmer, whereas a positive correlation was observed between TLR-4, OSI, and meiboscore and between TLR-4, OSI, and OSDI ( < 0.05). No correlation was found between the OSI and Schirmer results ( = 0.92). CONCLUSIONS: TLR-4 and oxidative stress both play important roles in OR pathophysiology and are closely related to clinical findings.
Phenotypic variability observed in a Chinese patient cohort with biallelic variants in the genes.
Zhang X, Xu K, Shi J … +5 more , Xie Y, Li N, Yan W, Jin ZB, Li Y
Mol Vis · 2024 · PMID 39563673
PURPOSE: The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( identified. The purpose of this study...
PURPOSE: The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( identified. The purpose of this study was to describe the genetic and clinical characteristics of a cohort of Chinese patients harboring biallelic variants in the genes. METHODS: We recruited 14 patients from 13 unrelated families who carried biallelic variants in the genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed to observe the effect of a novel non-canonical splice-site (NCSS) variant on pre-mRNA splicing. Eventually, eight patients were followed up. RESULTS: We detected 21 variants in three genes (, , and ); 13 variants were novel. RT-PCR assays indicated that the NCSS variant c.963-13A>G changed the pre-mRNA splicing, thereby creating an in-frame indel variant p.(W321delinsCPNLR) in . Diagnoses of neuronal ceroid lipofuscinosis (NCL) and non-syndromic retinal dystrophy (RD) were established in eight patients and six patients, respectively. The patients with NCL showed clinical heterogeneity, from typical phenotypes of CLN3 or CLN7 disease to juvenile- or adult-onset CLN1 disease. All patients experienced early and severe visual loss. A retinal evaluation revealed specific macular striation in 12 of the 14 patients. CONCLUSIONS: Patients with variants in the three genes exhibit varied clinical spectra, which might be related to their genotype. All patients presented relatively unique retinal alterations. Our findings point to a crucial need for genetic analysis for the early and accurate diagnosis of patients with NCL.
The effect of age on aqueous humor of humans with high myopia.
Wen K, Fu M, Li Y … +10 more , Zhang H, Wang X, Cai Y, Li Y, Su R, Huang Y, Liu M, Zhang Y, Zhao S, Sun J
Mol Vis · 2024 · PMID 39377095
BACKGROUND: High myopia is a common cause of vision loss. Age is an important factor in the development of high myopia. However, the effect of age on aqueous humor proteins in the context of high myopia is unknown. This...
BACKGROUND: High myopia is a common cause of vision loss. Age is an important factor in the development of high myopia. However, the effect of age on aqueous humor proteins in the context of high myopia is unknown. This study explored the effect of age on the aqueous humor protein of humans with high myopia. METHODS: The aqueous humor of high myopia patients of different ages with implantable collamer lens implantation (ICL) was collected. Data-independent acquisition proteomic analysis was employed to explore differentially expressed proteins (DEPs). Two different bioinformatics analysis methods were used to interpret the proteomic results. Furthermore, three proteins were confirmed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The study showed 18 upregulated and 20 downregulated proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the upregulated DEPs were highly enriched in coagulation and complement cascades. Weighted gene coexpression network analysis showed that the blue module was identified as a key module for high myopia and that the plasminogen (PLG) protein is a hub protein. ELISA confirmed that the expression levels of Alpha-1-antitrypsin were significantly upregulated in the aqueous humor of older patients presenting with high myopia. CONCLUSIONS: This is the first study to investigate the effect of age on the level of aqueous humor protein in high myopia. Our study provided a comprehensive data set on the overall protein changes of different ages of human high myopia, shedding light on its potential molecular mechanism in high myopia damage to the eyeball.
Retraction: Swati Arora, Nagendra Verma. Exosomal microRNAs as potential biomarkers and therapeutic targets in corneal diseases. Molecular Vision 2024; 30:92-106.
Mol Vis · 2024 · PMID 39286799
[This retracts the article on p. 92 in vol. 30, PMID: 38601014.].
[This retracts the article on p. 92 in vol. 30, PMID: 38601014.].
Precise longitudinal monitoring of corneal change through in vivo confocal microscopy in a rat dry eye disease model.
Chen M, Seo S, Simmons X … +4 more , Maroud Y, Wong T, Schubert W, Yiu SC
Mol Vis · 2024 · PMID 39076769
PURPOSE: While lacrimal gland removal is commonly used in animal models to replicate dry eye disease, research into systematically monitoring dry eye disease's longitudinal pathological changes is limited. In vivo confoc...
PURPOSE: While lacrimal gland removal is commonly used in animal models to replicate dry eye disease, research into systematically monitoring dry eye disease's longitudinal pathological changes is limited. In vivo confocal microscopy (Heidelberg Retina Tomograph 3 with a Rostock Cornea Module, Heidelberg Engineering Inc., Franklin, MA) can non-invasively reveal corneal histopathological structures. To monitor dry-eye-disease-related changes in corneal structures, we developed a precise monitoring method using in vivo confocal microscopy in a rat double lacrimal gland removal model. METHODS: Five Sprague-Dawley rats (age 8-9 weeks, male) underwent double lacrimal gland removal. Modified Schirmer's tear test, blink tests, and in vivo confocal microscopy images were acquired pre-surgery and at 1, 2, and 4 weeks post-surgery. Three individual stromal nerves were selected per eye as guide images, and images of the corresponding sub-basal nerve plexus area were acquired via volume acquisition. The same area was re-imaged in subsequent weeks. RESULTS: After double lacrimal gland removal, tear production was reduced by 60%, and the blink rate increased 10 times compared to pre-surgery. Starting from 1 week after surgery, in vivo confocal microscopy showed increased sub-basal nerve plexus nerve fiber density with inflammatory cell infiltration at the sub-basal nerve plexus layer and remained at an elevated level at 2 and 4 weeks post-surgery. CONCLUSIONS: We demonstrated that our precise monitoring method revealed detailed changes in the corneal nerves, the epithelium, and the stroma.
Uveal melanoma cell lines Mel270 and 92.1 exhibit a mesenchymal phenotype and sensitivity to the cytostatic effects of transforming growth factor beta in vitro.
Doudnikoff C, Leclerc D, Angenard G … +3 more , Gilot D, Coulouarn C, Mouriaux F
Mol Vis · 2024 · PMID 38601020
PURPOSE: Uveal melanoma (UM) is a deadly cancer with limited therapeutic options. At advanced stages, UM cells metastasize almost exclusively into the liver, where targeting metastatic UM cells remain a clinical challeng...
PURPOSE: Uveal melanoma (UM) is a deadly cancer with limited therapeutic options. At advanced stages, UM cells metastasize almost exclusively into the liver, where targeting metastatic UM cells remain a clinical challenge. Transforming growth factor beta (TGF-β) exhibits a functional duality in cancer, with one arm limiting tumor growth at an early stage and the second arm promoting metastasis at an advanced stage, notably by inducing an epithelial-to-mesenchymal transition. Thus, we hypothesized that targeting the TGF-β pathway could be relevant in the treatment of metastatic UM. METHODS: In this study, we first characterized the pseudoepithelial/mesenchymal phenotype of UM cell lines Mel270 and 92.1. We then treated the cell lines with TGF-β to evaluate their responsiveness to the cytokine and to characterize the functional impact of TGF-β on their cell viability. RESULTS: The results demonstrated, first, that the UM cell lines exhibited a mesenchymal phenotype and responded to TGF-β treatment in vitro and, second, that TGF-β promoted a cytostatic effect on the UM cell lines. CONCLUSIONS: Our findings indicate that UM cells are sensitive to the two arms of TGF-β signaling, which suggests that targeting the TGF-β pathway could be challenging in UM and would require a precise selection of patients in which only the prometastatic arm of TGF-β is activated.
The generation and characterization of a transgenic zebrafish line with lens-specific Cre expression.
Peng X, Jia X, Shang G … +5 more , Xue M, Jiang M, Chen D, Zhang F, Hu Y
Mol Vis · 2024 · PMID 38601019
PURPOSE: Danio rerio zebrafish constitute a popular model for studying lens development and congenital cataracts. However, the specific deletion of a gene with a Cre/LoxP system in the zebrafish lens is unavailable becau...
PURPOSE: Danio rerio zebrafish constitute a popular model for studying lens development and congenital cataracts. However, the specific deletion of a gene with a Cre/LoxP system in the zebrafish lens is unavailable because of the lack of a lens-Cre-transgenic zebrafish. This study aimed to generate a transgenic zebrafish line in which Cre recombinase was specifically expressed in the lens. METHODS: The pTol2 :Cre-polyA-:EGFP (enhanced green fluorescent protein) plasmid was constructed and co-injected with Tol2-transposase into one-to-two-cell-stage wild-type (WT) zebrafish embryos. Whole-mount in situ hybridization (ISH), tissue section, hematoxylin and eosin staining, a Western blot, a split-lamp observation, and a grid transmission assay were used to analyze the Cre expression, lens structure, and lens transparency of the transgenic zebrafish. RESULTS: In this study, we generated a transgenic zebrafish line, zTg(:Cre-:EGFP), in which Cre recombinase and EGFP were driven by the lens-specific promoter. zTg(:Cre-:EGFP) began to express Cre and EGFP specifically in the lens at the 22 hpf stage, and this ectopic Cre could efficiently and specifically delete the red fluorescent protein (RFP) signal from the lens when zTg(:Cre-:EGFP) embryos were injected with the -flanked RFP plasmid. The overexpression of Cre and EGFP did not impair zebrafish development or lens transparency. Accordingly, this zTg(:Cre-:EGFP) zebrafish line is a useful tool for gene editing, specifically with zebrafish lenses. CONCLUSIONS: We established a zTg(:Cre-:EGFP) zebrafish line that can specifically express an active Cre recombinase in lens tissues. This transgenic zebrafish line can be used as a tool to specifically manipulate a gene in zebrafish lenses.
Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy.
Betts JHJ, Troeberg L
Mol Vis · 2024 · PMID 38601018
Sorsby fundus dystrophy (SFD) is a rare, inherited form of macular degeneration caused by mutations in the gene encoding tissue inhibitor of metalloproteinases 3 (TIMP-3). There are 21 mutations currently associated with...
Sorsby fundus dystrophy (SFD) is a rare, inherited form of macular degeneration caused by mutations in the gene encoding tissue inhibitor of metalloproteinases 3 (TIMP-3). There are 21 mutations currently associated with SFD, with some variants (e.g., Ser179Cys, Tyr191Cys, and Ser204Cys) having been studied much more than others. We review what is currently known about the identified SFD variants in terms of their dimerization, metalloproteinase inhibition, and impact on angiogenesis, with a focus on disparities between reports and areas requiring further study. We also explore the potential molecular mechanisms leading to the accumulation of extracellular TIMP-3 in SFD and consider how accumulated TIMP-3 causes macular damage. Recent reports have identified extraocular pathologies in a small number of SFD patients. We discuss these intriguing findings and consider the apparent discrepancy between the widespread expression of TIMP-3 and the primarily retinal manifestations of SFD. The potential benefits of novel experimental approaches (e.g., metabolomics and stem cell models) in terms of investigating SFD pathology are presented. The review thus highlights gaps in our current molecular understanding of SFD and suggests ways to support the development of novel therapies.
Microstructure of the corneal endothelial transition zone in different laboratory animals.
Lee JS, Lee SY, Chin HS … +2 more , Kim NR, Jung JW
Mol Vis · 2024 · PMID 38601017
PURPOSE: To compare the microstructure of the corneal endothelial transition zone in different laboratory animals. METHODS: Flat-mount corneas of rabbits, rats, and mice were stained with Alizarin Red S (ARS) and observe...
PURPOSE: To compare the microstructure of the corneal endothelial transition zone in different laboratory animals. METHODS: Flat-mount corneas of rabbits, rats, and mice were stained with Alizarin Red S (ARS) and observed using scanning electron microscopy (SEM). The progenitor cell markers p75 neurotrophin receptor (p75NTR), SRY-box transcription factor 9 (SOX9), leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), telomerase reverse transcriptase (TERT), and proliferation marker K-67 were examined in the flat-mounted corneas of three laboratory animals using immunofluorescence microscopy. RESULTS: On flat mounts, proximity to the trabecular meshwork correlated with weaker ARS staining and greater polymorphism of endothelial cells in the transition zone in all animals. On SEM, distinct and smooth structures of the transition zone were negligibly detected in all animals. The endothelial cells in the transition zone had irregular shapes, with less dense, less wavy intercellular junctions, especially in murine corneas, exhibiting unique intercellular cystic spaces. In the transition zone of the rabbit cornea, progenitor cell markers p75NTR, SOX9, Lgr5, TERT, and proliferation marker K-67 were expressed, in contrast to those in other murine corneas. CONCLUSIONS: Although the transition zone was not identified clearly, irregular cell morphology and loss of cell-cell contact were observed in all animal corneal endothelial cells. The proliferative capacity and the presence of progenitor cells were confirmed in the transition zone, especially in the rabbit cornea.
Two novel non-coding single nucleotide variants in the DNase1 hypersensitivity site of causing North Carolina macular dystrophy in Korea.
Seo Y, Joo K, Lee J … +7 more , Diaz A, Jang S, Cherry TJ, Bujakowska KM, Han J, Woo SJ, Small KW
Mol Vis · 2024 · PMID 38601016
PURPOSE: Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families. METHODS: The regions associ...
PURPOSE: Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families. METHODS: The regions associated with NCMD were analyzed with genome sequencing, and variants were filtered based on the minor allele frequency (0.5%) and heterozygosity. Non-coding variants were functionally annotated using multiple computational tools. RESULTS: We identified two rare novel variants, chr6:g.99,598,914T>C (hg38; V17) and chr6:g.99,598,926G>A (hg38; V18) upstream of in families A and B, respectively. In Family 1, Grade 2 NCMD and a best-corrected visual acuity of 20/25 and 20/200 in the right and left eyes, respectively, were observed. In Family B, all affected individuals had Grade 1 NCMD with characteristic confluent drusen at the fovea and a best-corrected visual acuity of 20/20 in both eyes. These two variants are 10-22 bp downstream of the reported V10 variant within the DNase1 hypersensitivity site. This site is associated with progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypertrophy and lies in the putative enhancer site of . CONCLUSION: We identified two novel NCMD variants in the Korean population and further validated the regulatory role of the DNase1 hypersensitivity site upstream of .
EphB1 causes retinal damage through inflammatory pathways in the retina and retinal Müller cells.
Liu L, Jiang Y, Al-Shabrawey M … +3 more , Ren X, Wang S, Steinle JJ
Mol Vis · 2024 · PMID 38601015
PURPOSE: To examine whether increased ephrin type-B receptor 1 (EphB1) leads to inflammatory mediators in retinal Müller cells. METHODS: Diabetic human and mouse retinal samples were examined for EphB1 protein levels. Ra...
PURPOSE: To examine whether increased ephrin type-B receptor 1 (EphB1) leads to inflammatory mediators in retinal Müller cells. METHODS: Diabetic human and mouse retinal samples were examined for EphB1 protein levels. Rat Müller cells (rMC-1) were grown in culture and treated with EphB1 siRNA or ephrin B1-Fc to explore inflammatory mediators in cells grown in high glucose. An EphB1 overexpression adeno-associated virus (AAV) was used to increase EphB1 in Müller cells in vivo. Ischemia/reperfusion (I/R) was performed on mice treated with the EphB1 overexpression AAV to explore the actions of EphB1 on retinal neuronal changes in vivo. RESULTS: EphB1 protein levels were increased in diabetic human and mouse retinal samples. Knockdown of EphB1 reduced inflammatory mediator levels in Müller cells grown in high glucose. Ephrin B1-Fc increased inflammatory proteins in rMC-1 cells grown in normal and high glucose. Treatment of mice with I/R caused retinal thinning and loss of cell numbers in the ganglion cell layer. This was increased in mice exposed to I/R and treated with the EphB1 overexpressing AAVs. CONCLUSIONS: EphB1 is increased in the retinas of diabetic humans and mice and in high glucose-treated Müller cells. This increase leads to inflammatory proteins. EphB1 also enhanced retinal damage in response to I/R. Taken together, inhibition of EphB1 may offer a new therapeutic option for diabetic retinopathy.
Exosomal microRNAs as potential biomarkers and therapeutic targets in corneal diseases.
Arora S, Verma N
Mol Vis · 2024 · PMID 38601014
Exosomes are a subtype of extracellular vesicle (EV) that are released and found in almost all body fluids. Exosomes consist of and carry a variety of bioactive molecules, including genetic information in the form of mic...
Exosomes are a subtype of extracellular vesicle (EV) that are released and found in almost all body fluids. Exosomes consist of and carry a variety of bioactive molecules, including genetic information in the form of microRNAs (miRNAs). miRNA, a type of small non-coding RNA, plays a key role in regulating genes by suppressing their translation. miRNAs are often disrupted in the pathophysiology of different conditions, including eye disease. The stability and easy detectability of exosomal miRNAs in body fluids make them promising biomarkers for the diagnosis of different diseases. Additionally, due to the natural delivery capabilities of exosomes, they can be modified to transport therapeutic miRNAs to specific recipient cells. Most exosome research has primarily focused on cancer, so there is limited research highlighting the importance of exosomes in ocular biology, particularly in cornea-associated pathologies. This review provides an overview of the existing evidence regarding the primary functions of exosomal miRNAs and their potential role in diagnostic and therapeutic applications in the human cornea.
The importance of the fourth Greek key motif of human γD-crystallin in maintaining lens transparency-the tale told by the tail.
Vendra V, Thangapandian M
Mol Vis · 2024 · PMID 38586607
PURPOSE: Congenital cataract affects 1-15 per 10,000 newborns worldwide, and 20,000-40,000 children are born every year with developmental bilateral cataracts. Mutations in the crystallin genes are known to cause congeni...
PURPOSE: Congenital cataract affects 1-15 per 10,000 newborns worldwide, and 20,000-40,000 children are born every year with developmental bilateral cataracts. Mutations in the crystallin genes are known to cause congenital cataracts. Crystallins, proteins present in the eye lens, are made up of four Greek key motifs separated into two domains. Greek key motifs play an important role in compact folding to provide the necessary refractive index and transparency. The present study was designed to understand the importance of the fourth Greek key motif in maintaining lens transparency by choosing a naturally reported Y134X mutant human γD- crystallin in a Danish infant and its relationship to lens opacification and cataract. METHODS: Human γD-crystallin complementary DNA (cDNA) was cloned into the pET-21a vector, and the Y134X mutant clone was generated by site-directed mutagenesis. Wild-type and mutant proteins were overexpressed in the BL21 DE3 pLysS cells of . Wild-type protein was purified from the soluble fraction using the ion exchange and gel filtration chromatography methods. Mutant protein was predominantly found in insoluble fraction and purified from inclusion bodies. The structure, stability, aggregational, and amyloid fibril formation properties of the mutant were compared to those of the wild type using the fluorescence and circular dichroism spectroscopy methods. RESULTS: Loss of the fourth Greek key motif in human γD-crystallin affects the backbone conformation, alters the tryptophan micro-environment, and exposes a nonpolar hydrophobic core to the surface. Mutant is less stable and opens its Greek key motifs earlier with a concentration midpoint (C) of unfolding curve of 1.5 M compared to the wild type human γD-crystallin (C: 2.5 M). Mutant is capable of forming self-aggregates immediately in response to heating at 48.6 °C. CONCLUSIONS: Loss of 39 amino acids in the fourth Greek key motif of human γD-crystallin affects the secondary and tertiary structures and exposes the hydrophobic residues to the solvent. These changes make the molecule less stable, resulting in the formation of light-scattering particles, which explains the importance of the fourth Greek key in the underlying mechanism of opacification and cataract.
Impact of light-emitting diodes on visual cortex layer 5 pyramidal neurons (V1-L5PNs)-A rodent study.
Theruveethi N
Mol Vis · 2024 · PMID 38586606
PURPOSE: Light-induced neural retinal insult leads to alterations in the visual cortex neurons. We examined light-induced neuronal alterations in the visual cortex layer 5 pyramidal neurons (V1-L5PNs) of adult male Wista...
PURPOSE: Light-induced neural retinal insult leads to alterations in the visual cortex neurons. We examined light-induced neuronal alterations in the visual cortex layer 5 pyramidal neurons (V1-L5PNs) of adult male Wistar rats. METHODS: A total of 24 rats were divided into the following groups (n=6 each): control (NC), blue (BL), white (WL), and yellow (YL). The exposure groups were subjected to light-emitting diodes (LED) exposure (450-500 lx) of differing wavelengths for 90 days (12:12 16 light-dark cycle). After LED exposure, the animals were sacrificed, and the brain tissues were removed and impregnated in freshly prepared Golgi-Cox stain for 21 days. Sholl's grading analysis was used to quantify the apical and basal dendritic branching points and intersections of the V1-L5PNs. RESULTS: There was a significant difference in the number of apical branching points among all groups (p<0.001), with a particularly notable difference between the BL and WL groups (p<0.001). A post hoc test revealed that all exposure groups (BL, WL, and YL) had fewer apical branching points (p<0.001) on an average of 3.6 µm and a significant reduction in the dendritic intersections (p<0.001) compared to the number of branching points extending from layer Va (V1) neurons. CONCLUSIONS: Chronic and cumulative exposure to blue and white LEDs led to the pruning of V1-L5PNs, which might impair visual processing.
Clinical sequencing of the retinitis pigmentosa gene in over 1,000 cases of vision loss.
Pantrangi M, Rath J, Kaetterhenry N … +3 more , Branham K, Talsness D, Weber JL
Mol Vis · 2024 · PMID 38586605
pathogenic variants are the major cause of X-linked retinitis pigmentosa. Here, we report the results from 1,033 clinical DNA tests that included sequencing of . A total of 184 variants were identified: 78 pathogenic or...
pathogenic variants are the major cause of X-linked retinitis pigmentosa. Here, we report the results from 1,033 clinical DNA tests that included sequencing of . A total of 184 variants were identified: 78 pathogenic or likely pathogenic, 14 uncertain, and 92 likely benign or benign. Among the pathogenic and likely pathogenic variants, 23 were novel, and most were frameshift or nonsense mutations (87%) and enriched (67%) in exon 15 (ORF15). Identical pathogenic variants found in different families were largely on different haplotype backgrounds, indicating relatively frequent, recurrent mutations. None of the 16 mother/affected son pairs showed de novo mutations; all 16 mothers were heterozygous for the pathogenic variant. These last two observations support the occurrence of most mutations in the male germline.
Central subfield thickness of diabetic macular edema: Correlation with the aqueous humor proteome.
Cehofski LJ, Kojima K, Kusada N … +7 more , Hansen MS, Muttuvelu DV, Bakker N, Klaassen I, Grauslund J, Vorum H, Honoré B
Mol Vis · 2024 · PMID 38586604
PURPOSE: Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying molecular mechanisms. METHODS: In this study, a...
PURPOSE: Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying molecular mechanisms. METHODS: In this study, aqueous humor samples from eyes with treatment-naïve clinically significant DME (n = 13) and age-matched controls (n = 11) were compared with label-free liquid chromatography-tandem mass spectrometry. Additional aqueous humor samples from eyes with treatment-naïve DME (n = 15) and controls (n = 8) were obtained for validation by enzyme-linked immunosorbent assay (ELISA). Best-corrected visual acuity (BCVA) was evaluated, and the severity of DME was measured as central subfield thickness (CST) employing optical coherence tomography. Control samples were obtained before cataract surgery. Significantly changed proteins were identified using a permutation-based calculation, with a false discovery rate of 0.05. A human donor eye with DME and a control eye were used for immunofluorescence. RESULTS: A total of 101 proteins were differentially expressed in the DME. Regulated proteins were involved in complement activation, glycolysis, extracellular matrix interaction, and cholesterol metabolism. The highest-fold change was observed for the fibrinogen alpha chain (fold change = 17.8). Complement components C2, C5, and C8, fibronectin, and hepatocyte growth factor-like protein were increased in DME and correlated with best-corrected visual acuity (BCVA). Ceruloplasmin and complement component C8 correlated with central subfield thickness (CST). Hemopexin, plasma kallikrein, monocyte differentiation antigen CD14 (CD14), and lipopolysaccharide-binding protein (LBP) were upregulated in the DME. LBP was correlated with vascular endothelial growth factor. The increased level of LBP in DME was confirmed using ELISA. The proteins involved in desmosomal integrity, including desmocollin-1 and desmoglein-1, were downregulated in DME and correlated negatively with CST. Immunofluorescence confirmed the extravasation of fibrinogen at the retinal level in the DME. CONCLUSION: Elevated levels of pro-inflammatory proteins, including the complement components LBP and CD14, were observed in DME. DME was associated with the loss of basal membrane proteins, compromised desmosomal integrity, and perturbation of glycolysis.
Distribution of variants in patients with early onset glaucoma.
Gupta V, Panigrahi A, Somarajan BI … +9 more , Gupta S, Tripathy K, Singh A, Sharma A, Tandon R, Pradhan D, Sharma A, Kushwaha T, Inampudi KK
Mol Vis · 2023 · PMID 38577561
PURPOSE: To describe a novel association of variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome, as well as among other unrelat...
PURPOSE: To describe a novel association of variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome, as well as among other unrelated cases of juvenile onset open-angle glaucoma (JOAG) and primary congenital glaucoma (PCG). METHODS: This study of one family of GAPO with congenital glaucoma and three unrelated patients with JOAG analyzed a common link to glaucoma pathogenesis. Three girls with GAPO syndrome born to consanguineous parents in a multi-generation consanguineous family were identified. Two of the girls had congenital glaucoma in both eyes, while the elder sibling (a 10-year-old female) had features of GAPO syndrome without glaucoma. RESULTS: A genetic evaluation using whole exome sequencing revealed a novel homozygous mutation in all three affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense variant in the gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We found three other unrelated patients with JOAG and one patient with primary congenital glaucoma with no known glaucoma causing gene mutations, but having four different missense variants in the gene. One of these patients with JOAG had familial granular corneal dystrophy. Molecular dynamic simulations of TGFBI and 3-D structural models of three of its variants showed significant alterations that could influence TGFBI protein function. CONCLUSIONS: The possibility that variations in the gene could have a possible role in the pathogenesis of congenital and juvenile onset open-angle glaucomas needs further evaluation.
Toll-like receptor-4 expression and oxidative stress in ocular rosacea.
Yesilirmak N, Bukan N, Kurt B … +6 more , Fatsa T, Yuzbasıoglu S, Zhao M, Hosbul T, Bourges JL, Behar-Cohen F
Mol Vis · 2023 · PMID 38577560
PURPOSE: To investigate systemic and ocular toll-like receptor (TLR)-4 expression and its association with oxidative stress markers in ocular rosacea (OR). METHODS: This prospective study included 40 patients with rosace...
PURPOSE: To investigate systemic and ocular toll-like receptor (TLR)-4 expression and its association with oxidative stress markers in ocular rosacea (OR). METHODS: This prospective study included 40 patients with rosacea with ocular involvement and 20 healthy volunteers. Tear break-up time (TBUT), Schirmer test, meibomoscore, and ocular surface disease index (OSDI) scores were estimated for all participants. TLR-4 expression in conjunctival epithelium and peripheral blood mononuclear cells was quantified using real-time polymerase chain reaction (RT-PCR). In the tears and serum samples of all participants, antioxidant status (TAS), total oxidant status (TOS), and arylesterase (ARE) activation levels were measured using a fully automated spectrophotometric method, and the oxidative stress index (OSI) was calculated. RESULTS: TLR-4 expression levels and oxidative stress status (TOS and OSI values) were significantly higher (p < 0.01), and antioxidant status (TAS and ARE values) were significantly lower (p < 0.01) in both ocular and blood samples of patients with OR compared with those in controls. A significant positive correlation was found between the ocular and blood values in all parameters (p < 0.05). According to the clinical associations of these results, we found negative correlations between TLR-4, OSI, and TBUT and between TLR-4 and Schirmer, whereas a positive correlation was observed between TLR-4, OSI, and meiboscore and between TLR-4, OSI, and OSDI (p < 0.05). No correlation was found between the OSI and Schirmer results (p = 0.92). CONCLUSIONS: TLR-4 and oxidative stress both play important roles in OR pathophysiology and are closely related to clinical findings.
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