Molecular Vision最新文献

{"title":"Erratum: Ablation of C3 modulates macrophage reactivity in the outer retina during photo-oxidative damage.","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"204"},"PeriodicalIF":1.8,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637587","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":"Unravelling γD-crystallin aggregation pathway to understand cataract formation using fluorescence correlation spectroscopy.","authors":"Mangesh Bawankar, Bhaswati Sengupta, Sujata Malik, Pratik Sen, Ashwani K Thakur","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize the aggregation behavior of the γD-crystallin protein in an acidic environment with a focus on the formation of intermediate species. The research employs fluorescence correlation spectroscopy to unravel the intricate molecular events leading to aggregation, contributing to a comprehensive understanding of cataract formation.</p><p><strong>Methods: </strong>The kinetics of γD-crystallin protein aggregation were studied with a reversed-phase high-performance liquid chromatography sedimentation assay, a ThT binding assay, and light scattering. We used fluorescence correlation spectroscopy (FCS) to recognize intermediate aggregate species and characterized them with Fourier transform infrared spectroscopy (FTIR). Further, the morphologic characterization of aggregates was done by transmission electron microscopy (TEM), and their hydrophobic characteristics were analyzed using the 8-anilino-1-naphthalenesulfonic acid binding assay.</p><p><strong>Results: </strong>A negligible lag phase was observed in the aggregation kinetic experiments of the γD-crystallin protein. Pentamer, 25-mer, and higher oligomer intermediates were formed on the aggregation pathway. Conformation studies by FCS and FTIR have shown that oligomers are rich in cross-β sheet and random coil structure; however, they constitute more α-helix and less cross-β sheet structure than fibrils. TEM analysis revealed the approximate size of oligomers (diameter ~10 nm), protofibrils (~15 nm), and fibrils (~15 to ~35 nm).</p><p><strong>Conclusions: </strong>In this study, we reported the presence of various intermediate aggregate species formed on the aggregation pathway of γD-crystallin protein at low pH. This will open new areas of research in understanding the detailed aggregation mechanism and aggregation hotspot within unfolded γD-crystallin monomers. The insights gained will also pave the way for future research in the realm of amyloid formation in cataract.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"190-202"},"PeriodicalIF":1.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554017","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":"Mutation of beta-tubulin 4B gene (<i>TUBB4B)</i> causes autosomal dominant retinitis pigmentosa with sensorineural hearing loss in a multigenerational family.","authors":"Cheryl Y Gregory-Evans, Aaron W Joe, Kevin Gregory-Evans","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Members of a multigenerational Canadian family presented to an inherited retinal degeneration (IRD) clinic with retinitis pigmentosa (RP) and sensorineural hearing loss, reminiscent of an Usher syndrome phenotype. Biallelic disease-causing variants in the known Usher syndrome genes were not identified. Therefore, we enrolled further family members in this study and examined whether other IRD gene variants could explain the phenotype in the family.</p><p><strong>Methods: </strong>Family members underwent a comprehensive ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, fundus photography, visual field testing, spectral-domain optical coherence tomography, audiological examination, and genetic testing. Some patients also had autofluorescence imaging. Loss-of-function testing was initiated by antisense morpholino knockdown of <i>tubb4b</i> in zebrafish.</p><p><strong>Results: </strong>Multimodal clinical testing in affected patients revealed an autosomal dominant late-onset presentation of RP associated with progressive, bilateral sensorineural hearing loss that occurred in the second to third decades of life with no vestibular involvement. Panel-based genetic testing revealed a heterozygous c.1168C>T, p.Arg390Trp variant in the beta-tubulin 4B gene (<i>TUBB4B</i>) only in affected family members. Based on <i>in silico</i> analysis, segregation analysis through the family, and literature evaluation, this variant is likely to be the disease-causing variant inherited in an autosomal dominant manner. We searched our local database of ~1,000 patients with IRD, and no other <i>TUBB4B</i> variants were identified, confirming this is a rare disease variant. Knockdown of <i>tubb4b</i> in zebrafish revealed cone and rod photoreceptor abnormalities in the retina and hydrocephalus in the developing brain, resulting in early larval lethality.</p><p><strong>Conclusions: </strong>For the first time, we describe a multigenerational family with a <i>TUBB4B</i> gene variant p.(Arg390Trp) segregating with deaf-blindness, establishing autosomal dominant inheritance. This further confirms that the Arg390 codon is a mutation hotspot. We also expand the range of phenotypes seen with the p.(Arg390Trp) <i>TUBB4B</i> gene variant to include typical RP as well as a milder, pericentral RP. Furthermore, our studies suggest there is conservation of TUBB4B ciliary function between zebrafish and humans, making zebrafish a better model system for studying vision loss than the mouse model.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"175-188"},"PeriodicalIF":1.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554016","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":"Inhibitory effects of ursolic acid on oxygen-induced mouse retinal neovascularization via intravitreal injection.","authors":"Lu Yang, Fen Yang, Weiliang Zhang, Yanhua Wang, Peng Chen, Shufang Du, Xiaoyan Liu, Yan Gao, Junhua Shi, Peng Wang, Rui Li, Qiang Su","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Objective: This study aimed to explore the effects and mechanisms of ursolic acid (UA) on oxygen-induced retinal neovascularization (RNV) in mice and its inhibitory effects on human retinal capillary endothelial cells (HRCECs) under high-glucose conditions.</p><p><strong>Methods: </strong>Neonatal mice were divided into five groups: one normal group and four with oxygen-induced retinopathy (OIR), including OIR, phosphate-buffered saline, UA and Lucentis groups. On postnatal day 17 (P17), mice were euthanized and one eye was collected for retinal analysis using fluorescence microscopy. Protein and messenger ribonucleic acid (mRNA) levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-9 and cyclo-oxygenase-2 (COX-2) were detected. HRCECs cultured under high-glucose conditions were treated with UA to assess its effects on proliferation and molecular expression.</p><p><strong>Results: </strong>UA significantly reduced RNV area in OIR mice and protected astrocytes from hypoxia-induced damage (p<0.01). VEGF, MMP-2, MMP-9 and COX-2 levels were lower in the UA group compared with the OIR and phosphate-buffered saline groups (p<0.05), but slightly higher than in normal controls (p<0.01). Lucentis reduced VEGF levels but did not significantly affect MMP-2, MMP-9 or COX-2. In HRCECs, UA inhibited high-glucose-induced proliferation and reduced VEGF, MMP-2, MMP-9 and COX-2 expression in a time- and dose-dependent manner.</p><p><strong>Conclusions: </strong>UA inhibits RNV by reducing VEGF, MMP-2, MMP-9 and COX-2 expression, protecting astrocytes and suppressing HRCEC proliferation under high-glucose conditions, highlighting its therapeutic potential for retinal neovascular diseases.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"160-173"},"PeriodicalIF":1.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554015","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":"Subretinal delivery of AAV5-mediated human <i>Pde6b</i> gene ameliorates the disease phenotype in a rat model of retinitis pigmentosa.","authors":"Hee Jong Kim, Ji Hoon Kwak, Jun Sub Choi, Jin Kim, Seo Yun Moon, Steven Hyun Seung Lee, Heuiran Lee, Keerang Park, Joo Yong Lee, So-Yoon Won","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>A genetic disorder that affects the beta subunit of cyclic guanosine monophosphate-phosphodiesterase type 6 (PDE6B) in humans leads to autosomal recessive retinitis pigmentosa (RP). This condition causes severe vision loss in early life due to fast deterioration of photoreceptors. This study evaluated the therapeutic potential of subretinal delivery of the adeno-associated virus (AAV)5-mediated human <i>Pde6b</i> gene in an RP rat model caused by <i>Pde6b</i> gene knockout (KO).</p><p><strong>Methods: </strong>We compared the transduction efficiency and tropism of different AAV serotypes (2, 5 and 8) in <i>Pde6b</i> KO rats and found that AAV5 had the highest and most specific expression in photoreceptors. We injected AAV5-<i>Pde6b</i> into the subretinal space of <i>Pde6b</i> KO rats on postnatal day 21. We assessed the protective effects six weeks postinjection by measuring PDE6B protein expression, photoreceptor structure, retinal morphology and thickness, retinal pigment epithelium integrity and visual function.</p><p><strong>Results: </strong>AAV5-<i>Pde6b</i> treatment ameliorated the disease phenotype in <i>Pde6b</i> KO rats by restoring PDE6B protein expression, preserving photoreceptor structure, improving retinal morphology and thickness, and maintaining retinal pigment epithelium integrity. Functional analysis of vision by scotopic electroretinogram (ERG) and optokinetic nystagmus revealed that AAV5-<i>Pde6b</i> treatment significantly improved the visual function of <i>Pde6b</i> gene KO rats compared with AAV5-<i>GFP</i>-injected <i>Pde6b</i> KO rats.</p><p><strong>Conclusions: </strong>Our results demonstrate that AAV5-<i>Pde6b</i> may be a potential therapeutic gene candidate for RP caused by <i>Pde6b</i> mutations.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"127-141"},"PeriodicalIF":1.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094445","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":"Multikinase inhibition-mediated proliferative vitreoretinopathy therapy by nanoparticles in rabbits.","authors":"Elif Arslan, Faruk Ozturk, Burcu Uner, Serkan Tureli, Sevda Fatma Muftuoglu, Cetin Tas","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the efficacy of nanoparticles in treating proliferative vitreoretinopathy (PVR) through clinical observation, histology, and immunohistochemistry, despite unsatisfactory surgical outcomes and failed therapies for the current PVR treatment.</p><p><strong>Design: </strong>Twelve rabbits were divided into control and nintedanib (NTB) groups. The rabbits underwent weekly ophthalmologic examinations over a period of four weeks.</p><p><strong>Methods: </strong>At the end of the fourth week, the rabbits' eyes were removed for histological and immunohistochemical evaluation. Three additional rabbits outside the PVR model were administered a 0.5% NTB-loaded liposomal formulation in one eye. The drug concentrations in the vitreous samples were determined using high-pressure liquid chromatography on days 1, 7, 14, and 35.</p><p><strong>Results: </strong>The PVR stages were low in the NTB group, and there was no significant difference between the NTB and control groups (p = 0.108). However, it is worth noting that the group treated with NTB had significantly fewer epiretinal membrane formations during the histological evaluation. In addition, the corrected fluorescence intensity measurement of the subjects for collagen-1 in the NTB group was significantly lower than that in the control group (p = 0.004). Most importantly, no significant adverse effects were observed.</p><p><strong>Conclusions: </strong>Our study has provided preclinical support for a liposomal formulation containing NTB that, with single-dose administration, has the potential to be effective in vivo in preventing the development of PVR and its correlated pathologies without causing any significant side effects.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"142-157"},"PeriodicalIF":1.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094441","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":"Astragaloside IV improves the survival rates of retinal ganglion cells in traumatic optic neuropathy by regulating autophagy mediated by the AMPK-MTOR-ULK signaling pathway.","authors":"Wu Sun, Guojun Chao, Qiong Wu, Yanting Xia, Mengqiu Shang, Qiping Wei, Jian Zhou, Liang Liao","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Autophagy is involved in the pathological changes of traumatic optic neuropathy (TON), and the regulation of autophagy mediated by the AMPK-mTOR-ULK pathway is a potential therapeutic approach. Astragaloside IV (AS-IV) can regulate autophagy and play a therapeutic role in various diseases. This study aimed to observe the therapeutic effect of astragaloside on TON and the role of AMPK-MTOR-ULK pathway-mediated autophagy in this process.</p><p><strong>Methods: </strong>After the TON model was established, varying doses of AS-IV were administered as an intervention. Additionally, compound C (an AMPK inhibitor) or 3-methyladenine (an autophagy inhibitor) was administered intraperitoneally in conjunction with AS-IV. Samples were collected following a 7-day intervention period. Western blot analysis was conducted to measure the protein and phosphorylation levels of AMPK, mTOR, and ULK proteins. Moreover, western blot and quantitative reverse transcription PCR assays were used to quantify LC3 levels in retinal tissue. LC3 immunofluorescence was performed to examine autophagy levels in the ganglion cell layer (GCL), while transmission electron microscopy was employed to observe autophagosomes. Additionally, BRN3A immunofluorescence was used to label retinal ganglion cells (RGCs) in the GCL, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to assess apoptosis within the GCL. Finally, optic nerve conduction function was evaluated using flash visual evoked potentials.</p><p><strong>Results: </strong>After 7 days, the phosphorylation levels of AMPK, mTOR, and ULK proteins in retinal tissue exhibited significant changes following TON. AS-IV treatment enhanced LC3 messenger RNA and protein levels in TON model rats, and the autophagy-promoting effect of AS-IV was reversed by 3-methyladenine. Moreover, AS-IV elevated P-AMPK and P-ULK levels while decreasing P-mTOR levels. AS-IV also improved the survival rate of RGCs and reduced the P2 peak latency of flash visual evoked potentials. These effects were attenuated by the AMPK inhibitor compound C. Additionally, AS-IV increased the levels of AKT1 and P-AKT1 while decreasing P-S6RP levels in the retinal tissue of TON model rats.</p><p><strong>Conclusions: </strong>AS-IV can increase the survival rate of RGCs and improve visual function after TON, which may be related to the improvement of autophagy by regulating the AMPK-MTORC1-ULK pathway.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"99-112"},"PeriodicalIF":1.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094436","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":"Serum pro-brain natriuretic peptide correlates with optical coherence tomography indices in diabetic retinopathy.","authors":"Shivani Chaturvedi, Sandeep Saxena, Apjit Kaur, Pramod Kumar, Shivani Pandey, Abbas Ali Mahdi, Levent Akduman","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vascularization. The purpose of this study was to investigate the correlation of serum pro-BNP with optical coherence tomography (OCT) indices in diabetic retinopathy.</p><p><strong>Methods: </strong>This cross-sectional study investigated 96 consecutive subjects aged between 40 and 65 years: controls n = 24, no diabetic retinopathy (NoDR) n = 24, non-proliferative diabetic retinopathy (NPDR) n = 24, and proliferative diabetic retinopathy (PDR) n = 24. Same-day analysis of blood samples for serum pro-BNP levels was performed and spectral-domain OCT (SD-OCT) was used to measure the following OCT indices: OCT angiography (OCTA) superficial vessel density (SVD), deep vessel density (DVD), and foveal avascular zone (FAZ); OCT retinal nerve fiber layer (RNFL); and OCT ganglion cell analysis (GCA).</p><p><strong>Results: </strong>The mean serum pro-BNP levels for the control, NoDR, NPDR, and PDR groups were 14.07 ± 11.51, 27.35 ± 11.81, 280.44 ± 106.13, and 122.33 ± 43.66 pg/ml, respectively. The mean values of the various OCT parameters correlated with serum pro-BNP were OCTA SVD (r = <math><mo>-</mo></math> 0.360), OCTA DVD (r = 0.408), OCTA FAZ (r = 0.475), OCT RNFL (r = <math><mo>-</mo></math> 0.215) and OCT GCA (r = <math><mo>-</mo></math> 0.285; p<0.001).</p><p><strong>Conclusions: </strong>The serum pro-BNP levels were higher in the NPDR group than in the NoDR group and much lower in the PDR group than in the NPDR group, reflecting a lowering of the protective barrier. These results correlated with the changes in various OCT indices.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"114-125"},"PeriodicalIF":1.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094442","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":"DNA methyltransferase 1 regulates epithelial cell functions in corneal and eyelid development.","authors":"Antonius Christianto, Maureen Mongan, Bo Xiao, Qin Wang, Alvaro Puga, Michael L Robinson, Ying Xia","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>DNA methyltransferase 1 (DNMT1) is a crucial enzyme for the development of the retina and lens in the eye, but its roles in the cornea and eyelids are yet to be investigated.</p><p><strong>Methods: </strong>Ocular surface epithelium (OSE)-specific <i>Dnmt1</i> knockout mice, denoted as <i>Dnmt1^ΔOSE</i> , were generated. Prenatal eye tissues were characterized by hematoxylin and eosin staining; DNMT1 expression, DNA methylation, epithelial differentiation and cell-cell junctions were determined by immunohistochemistry; proliferation was assessed by 5-ethynyl 2´-deoxyuridin labeling and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Keratinocytes derived from <i>Dnmt1^F/F</i> mice were infected with adenoviruses carrying either green fluorescent protein or Cre recombinase to obtain wild-type and <i>Dnmt1-</i>deficient cells. In these cells, <i>Dnmt1</i> expression and epithelial terminal differentiation were evaluated by real-time PCR and/or western blotting; adherence junction and apoptosis were assessed by immunohistochemistry; proliferation was determined by 5-ethynyl 2´-deoxyuridin labeling; transcription factor activities were determined by luciferase reporter assays.</p><p><strong>Results: </strong>The abundant DNMT1 expression and cytosine methylation (5meC) detected in the ocular surface epithelia of wild-type embryos were largely diminished in that of <i>Dnmt1^ΔOSE</i> embryos. Besides lens degeneration, the <i>Dnmt1^ΔOSE</i> fetuses had severe abnormalities of the cornea and eyelids. The surface epithelial cells and stromal keratocytes in the knockout corneas were distorted and the eyelids failed to fuse in the knockout embryos, resulting in an eye-open-at-birth phenotype. At the cellular level, DNMT1-deficient OSE had normal proliferation but increased apoptosis and aberrant cell junctions. In addition, the knockout corneal epithelia failed to express corneal-specific keratin 12, and the knockout eyelid epithelia had increased expression of keratin 10, indicating accelerated terminal differentiation. In vitro studies validated that DNMT1 was required for epithelial cell survival, terminal differentiation and cell junctions, and further identified signaling pathways aberrantly activated by its ablation.</p><p><strong>Conclusion: </strong>DNMT1 maintains survival and differentiation of corneal and eyelid epithelium for the development of the eye.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"85-97"},"PeriodicalIF":1.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094437","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":"Syndromic forms of inherited retinal dystrophies: a comprehensive molecular diagnosis of consanguineous Pakistani families using capture panel sequencing.","authors":"Aleesha Asghar, Sumbal Wazir, Shehzeen Fatima, Hussan Bilal, Muhammad Shoaib, Saqib Ur Rehman, Sumaira Altaf, Yumei Li, Kiran Afshan, Rui Chen, Sabika Firasat","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Inherited retinal dystrophies (IRDs) represent a clinically and genetically heterogeneous group of genetic disorders that involve photoreceptors and/or retinal pigment epithelium degeneration. IRDs may occur as an isolated condition or may represent an ocular manifestation of a multisystemic disorder referred as syndromic IRD. To increase the understanding of the molecular determinants of syndromic IRD-related genes in the Pakistani population, we revealed the genetic profile of 13 consanguineous Pakistani families using capture panel sequencing.</p><p><strong>Methods: </strong>We performed comprehensive molecular testing on 72 IRD segregating Pakistani families using targeted capture panel sequencing of 344 known genes. The pathogenicity of candidate variants was assessed using American College of Medical Genetics and Genomics guidelines, followed by Sanger sequencing for segregation analysis.</p><p><strong>Results: </strong>Causative variants in previously reported syndromic IRDs genes were detected in 13/72 (18%) IRD families, including 5/72 (6.94%), 4/72 (5.55%), 2/72 (2.8%), 1/72(1.38%) and 1/72 (1.38%) in Usher syndrome, Bardet-Biedl syndrome, Batten disease, retinitis pigmentosa with situs inversus and Stickler syndrome segregated families, respectively. Disease-causing variants included nine previously reported and six novel homozygous variants, i.e., c.1143G>C in <i>USH2A</i>, c.470G>A in <i>MYO7A</i>, c.877-2A>G in <i>PCDH15</i>, c.347C>T in <i>ARL6</i>, c.581C>T in <i>CLN5</i> and c.100+1G>T in <i>ARL2BP</i> gene segregation with disease phenotype in eight families. Two heterozygous variants of the <i>USH2A</i> gene, i.e., c.12093C>A and c.9815C>T, were segregated in a compound heterozygous form in family RP243. Furthermore, RP151 showed segregation of a heterozygous variant c.247G>A in a Stickler syndrome gene, i.e., <i>COL2A1</i>, in an autosomal dominant manner.</p><p><strong>Conclusions: </strong>This study reaffirms the clinical and genetic heterogeneity of syndromic IRD-associated genes and confirms the usefulness of molecular methods in advancing our understanding of these conditions in consanguineous populations. The most commonly mutated Bardet-Biedl syndrome gene was <i>ARL6</i> (75%) and the most commonly mutated Usher syndrome genes were <i>USH2A</i> (40%) and <i>MYO7A</i> (40%). Our data could serve as a reference for future studies and the development of treatment modalities for affected families of Pakistani origin.</p>","PeriodicalId":18866,"journal":{"name":"Molecular Vision","volume":"31 ","pages":"69-83"},"PeriodicalIF":1.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094448","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}