Molecular Vision最新文献

{"title":"Epigenetic alterations associated with dexamethasone sodium phosphate through DNMT and TET in RPE cells.","authors":"Wenjie Liu,&nbsp;Sruthi Priya Mohan,&nbsp;Nareshkumar Ragavachetty Nagaraj,&nbsp;Shyam Sundar Jaganathan,&nbsp;Yi Wen,&nbsp;Sharada Ramasubramanyan,&nbsp;Joseph Irudayaraj","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To elucidate the mechanism behind epigenetic alteration associated with dexamethasone (DEX) sodium phosphate treatment.</p><p><strong>Methods: </strong>We performed enzyme-linked immunosorbent assay to quantify changes in global DNA methylation and hydroxymethylation, quantitative real-time PCR (qRT-PCR) of the DNA methylation- and hydroxymethylation-related gene, in vitro DNA methyltransferase (DNMT) enzymatic activity assays with purified DNMTs, and DNA hydroxymethylation pattern with super-resolution imaging.</p><p><strong>Results: </strong>We identified global DNA hypomethylation and hyper-hydroxymethylation upon DEX treatment, associated with aberrant mRNA expression levels of DNMT and ten-eleven translocation (TET) proteins. Additionally, DEX exposure could directly hinder DNMT activities.</p><p><strong>Conclusions: </strong>We showed that DEX-induced epigenetic alterations are linked to aberrant DNMT and TET expression, potentially through an essential role of DNMT.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"643-655"},"PeriodicalIF":2.2,"publicationDate":"2021-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/16/mv-v27-643.PMC8645185.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39850984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-tumor necrosis factor alpha reduces the proangiogenic effects of activated macrophages derived from patients with age-related macular degeneration.","authors":"Shira Hagbi-Levi,&nbsp;Liran Tiosano,&nbsp;Batya Rinsky,&nbsp;Nadav Levinger,&nbsp;Sarah Elbaz-Hayoun,&nbsp;Shai Carmi,&nbsp;Michelle Grunin,&nbsp;Itay Chowers","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Macrophages are believed to promote choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nvAMD); however, the underlying proangiogenic mechanism is poorly understood. Therefore, we examined this mechanism in proinflammatory macrophages derived from patients with nvAMD.</p><p><strong>Methods: </strong>Monocytes were isolated from patients with nvAMD and polarized to form an M1 proangiogenic phenotype. We then screened for the role of proangiogenic cytokines expressed by these macrophages, including TNF-α, VEGF, IL-6, IL-8, and IL-1β, using an ex vivo choroid sprouting assay and an in vivo rodent model of laser-induced CNV (LI-CNV). We also examined the value of inhibiting TNF-α inhibition with respect to reducing the proangiogenic effects of M1 macrophages. Finally, we analyzed the macrophage cytokine expression database to evaluate the feasibility of modulating the expression of TNF-α.</p><p><strong>Results: </strong>The cytokines above are expressed at high levels in patient-derived M1 macrophages. However, among the cytokines tested only TNF-α significantly increased choroid sprouting. Moreover, adoptive intravitreal transfer of M1 macrophages significantly increased LI-CNV, and blocking TNF-α abolished the proangiogenic effects of M1 macrophages in both models. An analysis of cytokine expression revealed that >50% of TNF-α expression is determined by modifiable factors.</p><p><strong>Conclusions: </strong>Blocking TNF-α can reduce the proangiogenic effects of M1 macrophages in nvAMD. Thus, activated macrophages may represent a potential therapeutic target for altering TNF-α expression in nvAMD.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"622-631"},"PeriodicalIF":2.2,"publicationDate":"2021-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d6/88/mv-v27-622.PMC8645186.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39850981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping retinal ganglion cell somas in a large-eyed glaucoma model.","authors":"Sara A Adelman,&nbsp;Kazuya Oikawa,&nbsp;Gopika Senthilkumar,&nbsp;Ralph Møller Trane,&nbsp;Leandro B C Teixeira,&nbsp;Gillian J McLellan","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to identify a robust, representative region of interest (ROI) for studies of retinal ganglion cell (RGC) soma loss in feline congenital glaucoma (FCG), a spontaneous, large-eyed glaucoma model.</p><p><strong>Methods: </strong>Seven FCG and three wild-type (wt) eyes were collected from 10 adult cats of both sexes. Eyes enucleated postmortem were immediately fixed overnight in 4% paraformaldehyde and then stored in 0.1 M PBS at 4 °C. The retinas were wholemounted, Nissl stained with cresyl violet, and imaged using light microscopy. Somas of RGCs were manually identified according to long-established morphological criteria and quantified using a semiautomated method; their coordinates were used to create density maps and plots of the retinal topography. The RGC axon counts for the corresponding eyes were obtained from glutaraldehyde-fixed, resin-embedded optic nerve cross-sections stained with 0.1% p-phenylenediamine (PPD) using a semiautomated counting method. Correlations between total optic nerve axons and RGC soma counts were assessed by linear regression. A k-means cluster algorithm was used to identify a retinal ROI, with further definition using a probability density algorithm.</p><p><strong>Results: </strong>Interindividual variability in RGC total soma counts was more pronounced in FCG cats (mean = 83,244, range: 0-155,074) than in wt cats (mean = 117,045, range: 97,373-132,972). In general, RGC soma counts were lower in FCG cats than they were in wt cats. RGC axon counts in the optic nerve cross-sections were lower than, but strongly correlated to, the total RGC soma count across all cats (in wt and FCG retinas; R² = 0.88) and solely FCG eyes (R² = 0.92). The k-means cluster algorithm indicated a region of the greatest mean difference between the normal wt retinas and FCG-affected retinas within the temporal retina, incorporating the region of the area centralis.</p><p><strong>Conclusions: </strong>As in other species, RGC soma count and topography are heterogeneous between individual cats, but we identified an ROI in the temporal retina for future studies of RGC soma loss or preservation in a large-eyed model of congenital glaucoma. Many of the methods refined and established to facilitate studies in this FCG model will be broadly applicable to studies in other large-eyed models.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"608-621"},"PeriodicalIF":2.2,"publicationDate":"2021-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0c/92/mv-v27-608.PMC8645189.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39615383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A convenient test system for the identification of CYP4V2 inhibitors.","authors":"Shishir Sharma,&nbsp;Sijie Liu,&nbsp;Pradeepraj Durairaj,&nbsp;David Machalz,&nbsp;Gerhard Wolber,&nbsp;Matthias Bureik","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Polymorphisms in the gene that codes for the human cytochrome P450 enzyme CYP4V2 are a cause of Bietti crystalline dystrophy (BCD). Therefore, inhibition of CYP4V2 activity may well be a cause of visual disability. However, monitoring the fatty acid hydroxylation reactions catalyzed by this enzyme is tedious and not well suited for inhibitor screening.</p><p><strong>Methods: </strong>We investigated the use of proluciferin compounds as probe substrates for efficient and convenient determination of CYP4V2 activity.</p><p><strong>Results: </strong>Ten proluciferins were tested for conversion by CYP4V2, and eight were found to be substrates of this enzyme. One point inhibitor assays were performed using luciferin 6' 3-furfuryl ether methyl ester (luciferin-3FEME) as the probe substrate and 12 test compounds. As expected, HET0016 had by far the strongest effect, while two other compounds (including osilodrostat) also displayed statistically significant inhibitory potency. The half maximal inhibitory concentration (IC₅₀) for HET0016 was determined to be 179 nM. A recently identified potent inhibitor of human CYP4Z1 was found not to inhibit CYP4V2. To explore the selectivity of this compound between CYP4Z1 and CYP4V2, we developed a homology model of CYP4V2 and conducted docking experiments.</p><p><strong>Conclusions: </strong>We provide the first protocol for a robust and convenient CYP4V2 inhibitor assay that does not depend on fatty acid analysis but can be simply monitored with luminescence. Moreover, we demonstrate additional evidence for the concern that compounds with CYP-inhibitory properties may inhibit CYP4V2 activity and thus, possibly cause visual disability.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"601-607"},"PeriodicalIF":2.2,"publicationDate":"2021-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d3/7f/mv-v27-601.PMC8598247.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39957596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A deep intronic substitution in <i>CNGB3</i> is one of the major causes of achromatopsia among Jewish patients.","authors":"Hamzah Aweidah,&nbsp;Manar Salameh,&nbsp;Claudia Yahalom,&nbsp;Anat Blumenfeld,&nbsp;Michal Macarov,&nbsp;Nicole Weisschuh,&nbsp;Susanne Kohl,&nbsp;Eyal Banin,&nbsp;Dror Sharon","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Although most (or even all) genes that can cause achromatopsia (ACHM) when mutated are known, some patients are still negative for mutations even after screening the coding sequence of all known genes. Our aim was to characterize the genetic and clinical aspects of a deep intronic (c.1663-1205G>A, IVS14-1205G>A) <i>CNGB3</i> variant.</p><p><strong>Methods: </strong>Clinical evaluation included visual acuity testing, refractive error, a full clinical eye exam, full-field electroretinography (ffERG), color vision testing, and retinal imaging. Genetic analysis of <i>CNGB3</i> exons, as well as part of intron 14, was performed by Sanger sequencing of PCR products.</p><p><strong>Results: </strong>Screening for the <i>CNGB3</i> c.1663-1205G>A variant revealed 17 patients belonging to 12 unrelated families who were either homozygous for this variant (7 cases, 5 families) or heterozygous in combination with another heterozygous known <i>CNGB3</i> mutation (10 cases, 7 families). All patients were diagnosed with cone-dominated disease, mainly complete ACHM. In all cases, the disease had an early, congenital onset. Visual acuity was markedly impaired, ranging between 0.07 and 0.32 on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (logarithm of the minimum angle of resolution [LogMAR] +1.18 to +0.50), with a mean visual acuity of 0.15 ETDRS (LogMAR +0.80). Additional typical signs of ACHM, including impaired color vision, light aversion, and nystagmus, were also noted in all patients. As is common in ACHM, fundus exams were largely unremarkable in most patients, with mild foveal RPE changes seen in some cases at older ages. ERG was available for 14 out of 17 patients, and in all of them-including infants from the age of 6 months-cone responses were nondetectable. In a few cases, rod involvement was also evident, with a mild reduction of amplitudes. Optical coherence tomography (OCT) imaging showed irregularity of the ellipsoid zone in the foveal area in some patients.</p><p><strong>Conclusions: </strong><i>CNGB3</i> is the most common cause of ACHM in patients of European descent; this is mainly due to a panethnic founder mutation, c.1148del. Here, we report on an intronic <i>CNGB3</i> variant that is more frequent than the c.1148del mutation in our cohort of Jewish patients. Among our ACHM cohort, 63.7% of patients had biallelic <i>CNGA3</i> mutations and 26.4% had biallelic <i>CNGB3</i> mutations. The phenotype of patients harboring the intronic mutation falls largely within the spectrum commonly seen in ACHM. Since gene therapy for <i>CNGB3</i> is currently under investigation, these patients might benefit from this promising therapy. Given that this variant is not detectable by current commonly used genetic testing platforms, these patients could easily be missed.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"588-600"},"PeriodicalIF":2.2,"publicationDate":"2021-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/26/mv-v27-588.PMC8477987.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39563310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemerin promotes microangiopathy in diabetic retinopathy via activation of ChemR23 in rat primary microvascular endothelial cells.","authors":"Li Jun,&nbsp;Song Lin-Lin,&nbsp;Song Hui","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>The correlation between chemerin and diabetic retinopathy (DR) has been demonstrated previously. We aimed to investigate the potential inflammatory and angiogenic roles of chemerin in DR using rat primary retinal microvascular endothelial cells (RRMECs).</p><p><strong>Methods: </strong>RRMECs were incubated in low- and high-glucose media, and stable chemerin receptor (ChemR23) knockdown in RRMECs was established by lentiviral infection. Real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were employed to investigate the mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and the interleukin-6 receptor (IL-6R) to explore the inflammatory and angiogenic effects of chemerin. A scratch assay was employed to evaluate the effect of chemerin on RRMEC migration.</p><p><strong>Results: </strong>Chemerin and TNF-α markedly increased the mRNA and protein expression of ICAM-1 in RRMECs (p<0.001). ChemR23 knockdown may have decreased the ICAM-1 expression under low- and high-glucose conditions (p<0.001). Even in the ChemR23-knockdown group, TNF-α significantly increased the mRNA and protein levels of ICAM-1 under low- and high-glucose conditions (p<0.001). Chemerin promoted VEGF expression under low- and high-glucose conditions. ChemR23 knockdown markedly decreased VEGF levels under low- and high-glucose conditions (p<0.05) and significantly decreased RRMEC migration (p<0.001).</p><p><strong>Conclusions: </strong>Chemerin promotes the expression of ICAM-1, the secretion of VEGF, and the migration of RRMECs via the activation of ChemR23.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"575-587"},"PeriodicalIF":2.2,"publicationDate":"2021-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a7/c3/mv-v27-575.PMC8421059.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39424974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated histamine levels in aqueous humor of patients with glaucoma.","authors":"Lakshminarayanan Gowtham,&nbsp;Nabanita Halder,&nbsp;Dewang Angmo,&nbsp;Sundararajan Baskar Singh,&nbsp;Rama Jayasundar,&nbsp;Tanuj Dada,&nbsp;Thirumurthy Velpandian","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Neurotransmitters (NTs) are the key mediators of essential ocular functions, such as processing the visual functions of the retina, maintaining homeostasis of aqueous humor, and regulating ocular blood flow. This study aims to determine variations in the levels of L-glutamate and γ-aminobutyric acid (GABA), histaminergic, adrenergic, cholinergic, and serotonergic NTs in patients with primary glaucoma versus patients with cataract.</p><p><strong>Methods: </strong>This case-control study involved three age-matched groups of patients with primary open angle glaucoma (POAG, n = 14), primary angle closure glaucoma (PACG, n = 21), and cataract (control, n = 19). Patients' aqueous humor and plasma were collected, snap frozen at -80 °C, and subjected to ultrasensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis for quantification of NTs.</p><p><strong>Results: </strong>Baseline intraocular pressure and the cup-to-disc ratio were found to be statistically significantly elevated in the POAG and PACG groups compared to the cataract control group. In aqueous humor, histamine was found to be statistically significantly elevated (5-fold, p<0.0001), whereas 1-methyl histamine was statistically significantly decreased (p<0.05) in POAG compared to the control group. A statistically significant increase in L-glutamate and GABA was observed among both patient groups with glaucoma compared to the cataract control group. Adrenaline was found to be elevated only in the PACG group (2.7-fold, p<0.05). No statistically significant difference was observed among the plasma NT levels between the groups.</p><p><strong>Conclusions: </strong>This study demonstrated the prominent role of the histaminergic system apart from autonomic mechanisms in the progression of glaucoma. Elevated L-glutamate and GABA could be due to retinal ganglionic cell death. Further studies are required to evaluate the effects of histamine on Müller cell dysfunction.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"564-573"},"PeriodicalIF":2.2,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ce/e4/mv-v27-564.PMC8421060.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39424973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mutations of the <i>PAX6</i>, <i>FOXC1</i>, and <i>PITX2</i> genes cause abnormal development of the iris in Vietnamese individuals.","authors":"Ha Hai Nguyen,&nbsp;Chau Minh Pham,&nbsp;Hoa Thi Thanh Nguyen,&nbsp;Nhung Phuong Vu,&nbsp;Trang Thu Duong,&nbsp;Ton Dang Nguyen,&nbsp;Bac Duy Nguyen,&nbsp;Hiep Van Nguyen,&nbsp;Hai Van Nong","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Congenital iris abnormality is a feature of several genetic conditions, such as aniridia syndrome and anterior segment degeneration (ASD) disorders. Aniridia syndrome is caused by mutations in the <i>PAX6</i> gene or its regulatory elements in the locus 11p13 or deletions of contiguous genes, while ASDs are the result of mutations in various genes, such as <i>PAX6</i>, <i>FOXC1</i>, <i>PITX2</i>, and <i>CYP1B1</i>. This study aims to identify pathogenic mutations in Vietnamese individuals with congenital anomalies of the iris.</p><p><strong>Methods: </strong>Genomic DNA was extracted from peripheral blood of 24 patients belonging to 15 unrelated families and their available family members. Multiplex ligation-dependent probe amplification (MLPA) was used to detect the deletions or duplications in the 11p13-14 region, including the <i>PAX6</i> gene and its neighboring genes. Direct PCR sequencing was used to screen mutations in 13 exons and flanking sequences of the <i>PAX6</i> gene. The patients without mutation in the <i>PAX6</i> locus were further analyzed with whole exome sequencing (WES). Identified mutations were tested with segregation analysis in proband family members.</p><p><strong>Results: </strong>We identified a total of 8 novel and 4 recurrent mutations in 20 of 24 affected individuals from 12 families. Among these mutations, one large deletion of the whole <i>PAX6</i> gene and another deletion of the <i>PAX6</i> downstream region containing the <i>DCDC1</i> and <i>ELP4</i> genes were identified. Eight mutations were detected in <i>PAX6</i>, including four nonsense, three frameshift, and one splice site. In addition, two point mutations were identified in the <i>FOXC1</i> and <i>PITX2</i> genes in patients without mutation in <i>PAX6</i>. Some of the mutations segregated in an autosomal dominant pattern where family members were available.</p><p><strong>Conclusions: </strong>This study provides new data on causative mutations in individuals with abnormal development of iris tissue in Vietnam. These results contribute to clinical management and genetic counseling for affected people and their families.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"555-563"},"PeriodicalIF":2.2,"publicationDate":"2021-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b2/f6/mv-v27-555.PMC8416135.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39451330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcome and genetic analysis of patients affected by retinal capillary hemangioblastoma in von Hippel Lindau syndrome.","authors":"Vittoria Murro,&nbsp;Myrta Lippera,&nbsp;Dario Pasquale Mucciolo,&nbsp;Letizia Canu,&nbsp;Tonino Ercolino,&nbsp;Giuseppina De Filpo,&nbsp;Dario Giorgio,&nbsp;Giovanna Traficante,&nbsp;Andrea Sodi,&nbsp;Gianni Virgili,&nbsp;Fabrizio Giansanti","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To describe genetic analysis, treatment results, and complications of patients affected by retinal capillary hemangioblastoma (RCH) in von Hippel Lindau (VHL) syndrome.</p><p><strong>Methods: </strong>We collected 17 patients with VHL syndrome, who underwent a molecular test and an ophthalmic evaluation at the Eye Clinic of the University Hospital of Florence from January 2005 to February 2020. We focused on eyes showing RCHs examined using color fundus photographs, fluorescein angiography, and optical coherence tomography.</p><p><strong>Results: </strong>Eight eyes of six patients (6/17; 35%) showed RCHs at the fundoscopic examination. All RCHs were treated with laser therapy. Three eyes underwent episcleral surgery, one eye showing vitreous hemorrhage received three intravitreal (IV) anti-VEGF injections and three cryotherapy procedures, and one eye underwent vitrectomy. In patients with RCHs, five were characterized by a truncating mutation of the VHL protein, and one patient showed a missense mutation. We have reported two VHL mutations not reported in literature.</p><p><strong>Conclusions: </strong>Patients with multiple RCHs, who developed RCH secondary effects, showed truncating mutations of the VHL protein. We recommend early screening and close monitoring, especially if RCHs are detected at presentation, for every patient with VHL syndrome independently of the results of the molecular test for a missense or a truncating mutation in <i>VHL</i>.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"542-554"},"PeriodicalIF":2.2,"publicationDate":"2021-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2a/9d/mv-v27-542.PMC8416136.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39451329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel mutation in <i>KIF11</i> with functional analysis in a cohort of 516 familial patients with exudative vitreoretinopathy.","authors":"Kezhou Wang,&nbsp;Xiang Zhang,&nbsp;Tian Tian,&nbsp;Peiquan Zhao","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To identify a novel mutation in <i>KIF11</i> with clinical and functional analysis among 516 familial patients with exudative vitreoretinopathy (FEVR).</p><p><strong>Methods: </strong>Next-generation sequencing was performed on 516 patients with FEVR between January 2015 and October 2017. Clinical data were collected from patient charts, including sex, age at presentation, visual acuity if available, axial length, stage, and systemic clinical findings. Protein and mRNA levels were detected with western blotting and real-time quantitative PCR, respectively. Mass spectrometry was used to analyze the interacting protein of KIF11.</p><p><strong>Results: </strong>In total, 304 of 516 patients were identified with at least one mutation in FEVR causative genes. Mutations in <i>KIF11</i> were identified in 14.47% of all carriers. The novel mutation p. H718L accounted for the greatest proportion (12/44; 27.30%) among all mutations in <i>KIF11</i>. Fundus presentations in these 12 individuals varied from the avascular zone of the peripheral retina to total retinal detachment. The p. H718L mutation can reduce the proliferation of human retinal endothelial cells (HRECs) compared to the wild type. The mRNA level of vascular endothelial growth factor-α, transforming growth factor-α, metalloproteinase-1, and angiopoietin-like 4 were depressed in the <i>KIF11</i> (p. H718L) groups under hypoxia stimuli. Mass spectrometry results demonstrated that eukaryotic elongation factor 2 (EEF2) was an interacting protein of KIF11 and that the p. H718L mutation can attenuate the binding activity.</p><p><strong>Conclusions: </strong>Patients with the most frequent <i>KIF11</i> mutation p. H718L showed typical FEVR presentations in this cohort. The mutation in <i>KIF11</i> likely plays a role in the proliferation of HRECs, and the p. H718L mutation can reduce the proliferation.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"27 ","pages":"528-541"},"PeriodicalIF":2.2,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/43/f6/mv-v27-528.PMC8410233.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39419434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}