Retinal Membranes Research Articles

Foveal microstructure and visual function in patients with lamellar macular hole, epiretinal membrane foveoschisis or macular pseudohole.

To compare the foveal microstructures, such as the prevalence of epiretinal proliferation (EP) and residual ellipsoid zone (EZ), in eyes with lamellar macular hole (LMH), epiretinal retinal membrane (ERM) foveoschisis and macular pseudohole (MPH), and to investigate the association of the foveal microstructure with visual functions. In addition to the prevalence of EP, we calculated the residual EZ index within 1mm and 3 mm (rEZ1 and rEZ3) in all examined eyes. Comparisons were conducted to baseline characteristics (logMAR visual acuity [logMAR VA], metamorphopsia score [Mave], central retinal thickness [CRT], the prevalence of EP, rEZ1 and rEZ3) between MPH, ERM foveoschisis and LMH subgroups. The relationships (1) between logMAR VA and each of age, type (MPH, ERM foveoschisis and LMH), the prevalence of EP, rEZ1, rEZ3, spherical equivalent (SE) and CRT and (2) between Mave and each of variables were investigated. Fifty-one eyes of 48 patients were enroled. The mean age was 65.2 ± 11.1 years. Ten eyes were diagnosed as LMH, 22 eyes as ERM foveoschisis and 19 eyes as MPH, respectively. There was a significant difference in CRT only between LMH and ERM foveoschisis (p = 0.023). There was a tendency toward significance in rEZ1 between LMH and ERM foveoschisis (p = 0.057), but not in rEZ3. The optimal model for logMAR VA included age, rEZ1, SE and CRT. On the other hand, the optimal model for Mave included the prevalence of EP, rEZ1 and SE. Microstructural observations are useful to predict visual functions in LMH, ERM foveoshisis and MPH.

Inflammatory retinal and choroidal neovascularization in a case of post-fever immune retinitis

The development of retinal and choroidal neovascularization in posterior uveitis is attributed to the angio-inflammatory drive with/without ruptures in the retinal pigment epithelium-Bruch's membrane complex. We report a unique case of a 15-year-old Asian-Indian female who developed immune retinitis post-typhoid fever along with simultaneous retinal and choroidal neovascularization. After ruling out infectious etiologies, she was initiated on a course of systemic steroids considering that the retinitis had immune-mediated pathogenesis. Subsequently, the retinitis lesion and choroidal neovascular membrane healed with scarring while the retinal neovascular complex showed fibrotic regression.

Primary Antiphospholipid Syndrome: A Hidden Predisposing Factor for Retinal Vein Occlusion and Choroidal Neovascular Membrane Formation Among Young Population

Background & Objectives: Antiphospholipid syndrome can lead to variable systemic and ophthalmic manifestations. The study aims to establish the relationship between retinal vein occlusion (RVO) or choroidal neovascular membrane (CNVM) with Antiphospholipid Syndrome (APS). Methods: A multicentric prospective cross-sectional study was carried out in three major eye centers in Bahrain that included The Eye Infirmary, Bahrain Royal Hospital, and King Hamad University Hospital. All young patients aging from 35 to 50 years, presenting with either RVO or CNVM and not known to have any underlying systemic disease were included in the study. Antiphospholipid confirmatory tests and coagulation profiles were done for all patients. Results: Total number of fourteen eyes of ten patients were enrolled in the study. Six patients had RVO, three out of them had central retinal vein occlusion (CRVO) and three had branch retinal vein occlusion (BRVO). Four patients had bilateral CNVM (total of 8 eyes). All patients recorded high activated partial thromboplastin time (aPTT) readings, six out of ten patients were labeled as primary APS, four of them had positive anti-cardiolipin antibodies and the other two patients were positive for plasma lupus anticoagulant. Conclusion: APS should be considered as an etiological factor in all cases of retinal vein occlusion and choroidal neovascular membrane affecting young otherwise healthy individuals. In this study, 60% of patients who fit the inclusion criteria were labeled as primary APS patients. Timely investigations and treatment in these cases can prevent major catastrophic thrombotic events which may involve any system or organ in the body. Keywords: Antiphospholipid syndrome, Blood coagulation tests, Eye, Lupus coagulation inhibitor, Retinal vein occlusion

Retinal degeneration-3 protein attenuates photoreceptor degeneration in transgenic mice expressing dominant mutation of human retinal guanylyl cyclase

Different forms of photoreceptor degeneration cause blindness. Retinal degeneration-3 protein (RD3) deficiency in photoreceptors leads to recessive congenital blindness. We proposed that aberrant activation of the retinal membrane guanylyl cyclase (RetGC) by its calcium-sensor proteins (guanylyl cyclase–activating protein [GCAP]) causes this retinal degeneration and that RD3 protects photoreceptors by preventing such activation. We here present in vivo evidence that RD3 protects photoreceptors by suppressing activation of both RetGC1 and RetGC2 isozymes. We further suggested that insufficient inhibition of RetGC by RD3 could contribute to some dominant forms of retinal degeneration. The R838S substitution in RetGC1 that causes autosomal-dominant cone–rod dystrophy 6, not only impedes deceleration of RetGC1 activity by Ca2+GCAPs but also elevates this isozyme's resistance to inhibition by RD3. We found that RD3 prolongs the survival of photoreceptors in transgenic mice harboring human R838S RetGC1 (R838S+). Overexpression of GFP-tagged human RD3 did not improve the calcium sensitivity of cGMP production in R838S+ retinas but slowed the progression of retinal blindness and photoreceptor degeneration. Fluorescence of the GFP-tagged RD3 in the retina only partially overlapped with immunofluorescence of RetGC1 or GCAP1, indicating that RD3 separates from the enzyme before the RetGC1:GCAP1 complex is formed in the photoreceptor outer segment. Most importantly, our in vivo results indicate that, in addition to the abnormal Ca2+ sensitivity of R838S RetGC1 in the outer segment, the mutated RetGC1 becomes resistant to inhibition by RD3 in a different cellular compartment(s) and suggest that RD3 overexpression could be utilized to reduce the severity of cone–rod dystrophy 6 pathology.

Assignment Flow for Order-Constrained OCT Segmentation

At the present time optical coherence tomography (OCT) is among the most commonly used non-invasive imaging methods for the acquisition of large volumetric scans of human retinal tissues and vasculature. The substantial increase of accessible highly resolved 3D samples at the optic nerve head and the macula is directly linked to medical advancements in early detection of eye diseases. To resolve decisive information from extracted OCT volumes and to make it applicable for further diagnostic analysis, the exact measurement of retinal layer thicknesses serves as an essential task be done for each patient separately. However, manual examination of OCT scans is a demanding and time consuming task, which is typically made difficult by the presence of tissue-dependent speckle noise. Therefore, the elaboration of automated segmentation models has become an important task in the field of medical image processing. We propose a novel, purely data driven geometric approach to order-constrained 3D OCT retinal cell layer segmentation which takes as input data in any metric space and can be implemented using only simple, highly parallelizable operations. As opposed to many established retinal layer segmentation methods, we use only locally extracted features as input and do not employ any global shape prior. The physiological order of retinal cell layers and membranes is achieved through the introduction of a smoothed energy term. This is combined with additional regularization of local smoothness to yield highly accurate 3D segmentations. The approach thereby systematically avoid bias pertaining to global shape and is hence suited for the detection of anatomical changes of retinal tissue structure. To demonstrate its robustness, we compare two different choices of features on a data set of manually annotated 3D OCT volumes of healthy human retina. The quality of computed segmentations is compared to the state of the art in automatic retinal layer segmention as well as to manually annotated ground truth data in terms of mean absolute error and Dice similarity coefficient. Visualizations of segmented volumes are also provided.

Monocular Vision-Based Retinal Membrane Peeling With a Handheld Robot.

Retinal membrane peeling requires delicate manipulation. The presence of the surgeon's physiological tremor, the high variability and often low quality of the ophthalmic image, and excessive forces make the tasks more challenging. Preventing unintended movement caused by tremor and unintentional forces can reduce membrane injury. With the use of an actively stabilized handheld robot, we employ a monocular camera-based surface reconstruction method to estimate the retinal plane and we propose the use of a virtual fixture with the application of a hard stop and motion scaling to improve control of the tool tip during delaminating in a laboratory simulation of retinal membrane peeling. A hard stop helps to limit downward force exerted on the surface. Motion scaling also improves the user's control of contact force when delaminating. We demonstrate a reduction of maximum force and maximum surface-penetration distance from the estimated retinal plane using the proposed technique.

Expression and role of P-element-induced wimpy testis-interacting RNA in diabetic-retinopathy in mice.

BACKGROUNDAs one of the major microvascular complications of diabetes, diabetic retinopathy (DR) is the leading cause of blindness in the working age population. Because the extremely complex pathogenesis of DR has not been fully clarified, the occurrence and development of DR is closely related to tissue ischemia and hypoxia and neovascularization The formation of retinal neovascularization (RNV) has great harm to the visual acuity of patients.AIMTo investigate the expression of P-element-induced wimpy testis-interacting RNA (piRNA) in proliferative DR mice and select piRNA related to RNV.METHODSOne hundred healthy C57BL/6J mice were randomly divided into a normal group as control group (CG) and proliferative DR (PDR) group as experimental group (EG), with 50 mice in each group. Samples were collected from both groups at the same time, and the lesions of mice were evaluated by hematoxylin and eosin staining and retinal blood vessel staining. The retinal tissues were collected for second-generation high-throughput sequencing, and the differentially expressed piRNA between the CG and EG was detected, and polymerase chain reaction (PCR) was conducted for verification. The differentially obtained piRNA target genes and expression profiles were enrichment analysis based on gene annotation (Gene Ontology) and Kyoto Encyclopedia of Genes and Genomes.RESULTSIn the CG there was no perfusion area, neovascularization and endothelial nucleus broke through the inner boundary membrane of retinap. In the EG, there were a lot of nonperfused areas, new blood vessels and endothelial nuclei breaking through the inner boundary membrane of the retina. There was a statistically significant difference in the number of vascular endothelial nuclei breaking through the inner retinal membrane between the two groups. High-throughput sequencing analysis showed that compared with the CG, a total of 79 piRNAs were differentially expressed in EG, among which 43 piRNAs were up-regulated and 36 piRNAs were down-regulated. Bioinformatics analysis showed that the differentially expressed piRNAs were mainly concentrated in the signaling pathways of angiogenesis and cell proliferation. Ten piRNAs were selected for PCR, and the results showed that the expression of piR-MMU-40373735, piR-MMU-61121420, piR-MMU-55687822, piR-MMU-1373887 were high, and the expression of piR-MMU-7401535, piR-MMU-4773779, piR-MMU-1304999, and piR-MMU-5160126 were low, which were consistent with the sequencing results.CONCLUSIONIn the EG, the abnormal expression of piRNA is involved in the pathway of angiogenesis and cell proliferation, suggesting that piRNAs have some regulatory function in proliferative diabetic-retinopathy.

Nano-scale resolution of native retinal rod disk membranes reveals differences in lipid composition.

Photoreceptors rely on distinct membrane compartments to support their specialized function. Unlike protein localization, identification of critical differences in membrane content has not yet been expanded to lipids, due to the difficulty of isolating domain-specific samples. We have overcome this by using SMA to coimmunopurify membrane proteins and their native lipids from two regions of photoreceptor ROS disks. Each sample's copurified lipids were subjected to untargeted lipidomic and fatty acid analysis. Extensive differences between center (rhodopsin) and rim (ABCA4 and PRPH2/ROM1) samples included a lower PC to PE ratio and increased LC- and VLC-PUFAs in the center relative to the rim region, which was enriched in shorter, saturated FAs. The comparatively few differences between the two rim samples likely reflect specific protein-lipid interactions. High-resolution profiling of the ROS disk lipid composition gives new insights into how intricate membrane structure and protein activity are balanced within the ROS, and provides a model for future studies of other complex cellular structures.

Three-dimensional shape analysis of peripapillary retinal pigment epithelium-basement membrane layer based on OCT radial images

Abstract The peripapillary retinal pigment epithelium-basement membrane (ppRPE/BM) layer angle was recently proposed as a potential index for estimating intracranial pressure noninvasively. However, the ppRPE/BM layer angle, measured from the optical coherence tomography (OCT) scans, varied across the radial directions of the optic disc. This made the ppRPE/BM layer angle difficult to be utilized in its full potential. In this study, we developed a mathematical model to quantify the ppRPE/BM layer angles across radial scans in relation to the ppRPE/BM 3D morphology in terms of its 3D angle and scanning tilt angles. Results showed that the variations of the ppRPE/BM layer angle across radial scans were well explained by its 3D angle and scanning tilt angles. The ppRPE/BM layer 3D angle was reversely fitted from the measured ppRPE/BM layer angles across radial directions with application to six eyes from four patients, who underwent medically necessary lumbar puncture. The fitted curve from our mathematical model matched well with the experimental measurements (R 2 > 0.9 in most cases). This further validated our mathematical model. The proposed model in this study has elucidated the variations of ppRPE/BM layer angle across 2D radial scans from the perspective of the ppRPE/BM layer 3D morphology. It is expected that the ppRPE/BM layer 3D angle developed in this study could be further exploited as a new biomarker for the optic disc.

EXPERIENCE OF COMBINED LASER TREATMENT IN COMPLICATED PERIPHERAL VITROCHORIORETINAL DYSTROPHIES

Currently, one of the topical subjects of ophthalmology is the study of morphological features of the vitreoretinal interface. Peripheral changes encompass a range of entities, from incidental findings to retinal detachment. Therefore, diagnosis and treatment in the zone of the peripheral interface seem relevant.Keywords: peripheral vitreochorioretinal dystrophy, regmatogenic retinal detachment, inner retinal border membrane, vitreoretinal interface, optical coherence tomography, restrictive retinal laser coagulation, laser tractotomy.

Targeted Noninvasive Treatment of Choroidal Neovascularization by Hybrid Cell-Membrane-Cloaked Biomimetic Nanoparticles.

Choroidal neovascularization (CNV) is the leading cause of vision loss in many blinding diseases, but current antiangiogenic therapies with invasively intravitreal injection suffer from poor patient compliance and a rate of devastating ocular complications. Here, we develop an alternative antiangiogenic agent based on hybrid cell-membrane-cloaked nanoparticles for noninvasively targeted treatment of CNV. The retinal endotheliocyte membrane coating provides as-fabricated nanoagents with homotypic targeting capability and binding ability to the vascular endothelial growth factor. The fusion of red blood cell membranes protects the hybrid membrane-coated nanoparticles from phagocytosis by macrophages. In a laser-induced wet age-related macular degeneration mouse model, a significantly enhanced accumulation is observed in CNV regions after intravenous delivery of the hybrid membrane-coated nanoparticles. Moreover, an excellent therapeutic efficacy is achieved in reducing the leakage and area of CNV. Overall, the biomimetic antiangiogenic nanoagents provide an effective approach for noninvasive treatment of CNV.

Large air bubble in the Berger space during cataract surgery

For treating retinal or Descemet membrane detachment, an expansive gas is purposefully injected into the vitreous cavity or the anterior chamber. However, it is important to consider the potential complications associated with gas injection, such as intraocular pressure elevation, intraocular lens (IOL) opacification, and gas bubble migration. It is crucial to deal effectively with unexpected intraocular air bubbles. The Berger space is an interspace between the posterior lens capsule and the anterior vitreous hyaloid that provides potential for gas bubble migration. In this study, the features and management during cataract surgery for an individual with a large air bubble in the Berger space is described. A 26-gauge needle was used to puncture the posterior capsule and aspirate the gas bubble; however, this intraoperative strategy was considered inappropriate. Other strategies, such as pars plana aspiration and posterior capsule capsulorhexis before IOL implantation, may be considered in similar cases in the future.

Hydration Drives Activation of the G‐Protein‐Coupled Receptor Rhodopsin

G-protein-coupled receptors (GPCRs) are a pivotal superfamily of seven-helix transmembrane receptors responsible for the transduction of stimuli across cellular membranes. They are the targets of ~30% of the pharmaceuticals currently in the market. Understanding how the soft membrane matter (lipids and water) influences the structural changes during the activation of GPCRs is crucial to discovering and developing novel GPCR-targeted drugs [1]. Here, we assessed the effects of hydration on the conformational dynamics of GPCRs by subjecting the archetypical GPCR-rhodopsin in native retinal disk membranes to varying osmotic pressures using polyethylene glycol (PEG) solutions of different molar mass [2,3]. The metastable activation equilibrium of rhodopsin (Keq) after photoexcitation was quantified using UV-visible spectroscopy. Analysis of the results using thermodynamic relations revealed for the first time an influx of ~80-100 water molecules flooding into the rhodopsin interior during photoactivation, validating previous molecular dynamics (MD) simulations [4]. Both applied osmotic pressure and the osmolyte size affected the metarhodopsin equilibrium. Dehydrating conditions generally favored the closed inactive Meta-I state through an efflux of water from the protein interior, while small penetrating osmolytes stabilized the expanded active Meta-II conformation in low concentration regimes. The pH titration curves for the metarhodopsin equilibrium in the presence of various PEG osmolytes showed that hydration is coupled to activation via modulation of the pKA of Glu134 of the conserved E(D)RY sequence motif. By changing water availability, osmotic stress perturbs the dielectric constant characterizing the Glu134 microenvironment and the thermodynamics of its protonation. Activation of rhodopsin is contingent upon the change in electrostatic microenvironments by rearranging water molecules within the protein conformation, dramatically recasting the role of soft matter in biological signal transduction. [1] M.F. Brown (2017) Annu. Rev. Biophys. 46, 379-410. [2] U. Chawla et al. (2020) Angew. Chem. Int. Ed. doi:10.1002/anie.202003342. [3] N. Weerasinghe et al. (2018) Biophys. J. 114, 274a. [4] N. Leioatts et al. (2014) Biochemistry 53, 376−385.

The detection of COAT’s disease at its early stage and management

Coats disease is the potential leading cause of blindness which is an idiopathic disorder characterized by progressive deposition of intraretinal or subretinal exudates and abnormal development of retinal vasculatures known as telangiectasia that leads to exudative retinal detachment. The case shows unilateral involvement of the eye and primarily at an early age of 12 years. The cause of the disease is idiopathic and if associated with other genetic disorders emphasizes the deposition of a genetic component. The underlying histopathological problem is thought due to the abnormal permeability of capillary endothelial cells of the retina. The complications of long-standing disease may progress to total retinal detachment, leukocoria, painful Glaucoma and can be hard to differentiate from retinoblastoma. The diagnostic tools are indirect ophthalmoscopy, fluorescein angiography, CT scan, and MRI. The treatment depends on the closure of abnormal leaking vessels of the retina which is laser therapy and anti-VEGF at its early stage. The advanced stage requires surgical therapy such as scleral buckling, pars plana vitrectomy, and anterior vitrectomy for reattachment of the retina or pre retinal membrane. A careful selection therapy showed a 70% improvement in the clinical course of the disease

Management of Vasoproliferative Tumors of the Retina with Macular Complications by Pars Plana Vitrectomy Combined with Episcleral Cryotherapy.

Objective To evaluate the efficacy of pars plana vitrectomy (PPV) combined with episcleral cryotherapy in treating vasoproliferative tumors of the retina (VPTR) with macular complications. Methods In this retrospective noncomparative interventional case-series analysis, we included 11 eyes of ten patients diagnosed with VPTR. All patients underwent comprehensive ophthalmic examinations and were treated with PPV combined with episcleral cryotherapy. Best-corrected visual acuity (BCVA), tumor activity, retinal morphological structure, and postoperative complications were evaluated. Results Macular complications included epimacular membrane (n = 10), macular hole (n = 3), and macular edema (n = 1). Tumors were treated with triple freeze-thaw episcleral cryotherapy during PPV. The mean logarithm of minimal angle of resolution (logMAR) BCVA dropped from 0.62 ± 0.58 to 0.39 ± 0.46. The difference between the mean values of logMAR BCVA before and after treatment was statistically significant (t = 2.48, P=0.033). The tumor activity was controlled effectively in nine cases. Compared with preoperative tumor activity, tumor activity after treatment was significantly lower (P < 0.01). The increase of central retinal thickness and the disruption of retinal layers were associated with macular holes, macular edema, and retinal proliferative membrane. After the treatment, visual acuity improved in 91% of the cases, and 73% had no long-term complications. Conclusion PPV combined with episcleral cryotherapy promoted tumor regression, preserved retinal integrity, and improved visual acuity. Thus, the combination of PPV with episcleral cryotherapy can be considered effective and safe for the management of VPTR with macular complications.

Long-term Outcomes of Ophthalmic and Retinal Artery Occlusion After Cosmetic Facial Filler Injection.

Ophthalmic artery occlusion (OAO) and retinal artery occlusion (RAO) after facial filler injection have become increasingly significant due to the growth in cosmetic injection procedures for aesthetic purposes. The aim of this study was to analyze the long-term visual outcomes and complications of cosmetic facial filler-related OAO and RAO. This single-center, retrospective case series included 17 eyes of 16 filler-related OAO or RAO patients with a follow-up period of 1 year or longer. Main outcome measures were best-corrected visual acuity (BCVA) and long-term complications. The mean [standard deviation] age at diagnosis was 31.7 [9.7] years; all the patients were female. The mean follow-up period was 5.4 [2.4] years. The mean BCVA was 2.34 and 2.41 logMAR at the initial and final visits, respectively, which indicates sustained long-term visual impairment. Ocular complications included retinal atrophy and degeneration (100.0%), optic atrophy and blindess (no light perception) (82.4%), strabismus (80.0%), retinal fibrous membrane (68.8%), posterior synechiae (35.3%), neovascularization (29.4%), iris atrophy and cataract (23.5%), corneal opacity and phthisis bulbi (17.6%), visual field defect and iris defect (11.8%), ophthalmoplegia (7.7%), and pupillary block (5.9%). Extraocular complications of brain infarction and depression were found in 25.0%, whereas skin necrosis was found in 13.3% of patients. Facial filler-related OAO or RAO resulted in long-term poor visual outcome, and most of the patients experienced irreversible visual impairment with no light perception despite various treatments. Various long-term ocular and extraocular complications were observed, which should be monitored for a long-term follow-up period. Our findings suggest that prevention should be emphasized more than treatment.

The Outer Retinal Membrane Protein 1 Could Inhibit Lung Cancer Progression as a Tumor Suppressor.

Some related reports indicate that the outer retinal membrane protein 1 (ROM1) functions importantly in the regulation of the biological process of tumor. Nevertheless, studies towards the role of ROM1 in lung cancer are few. Here, our data demonstrated that ROM1 displayed a relation with lung cancer tumorigenesis and development. In the Tumor Genome Atlas (TCGA) cohort, reduced ROM1 level was observed in lung cancer tissues, instead of normal tissues. After bioinformatics analysis, the data revealed that ROM1 level was associated with the tumor stage. Additional results indicated that highly expressed ROM1 exhibited a positive correlation with the overall survival rate, and ROM1 was probably a promising prognostic biomarker of lung cancer. Additionally, our results indicated that knocking out ROM1 could promote cell proliferation, migration, and invasion. Our data conclusively demonstrated that ROM1 modulated lung cancer tumorigenesis and development, as a prognosis and treatment biomarker.

Presumed Natural History of Combined Hamartoma of the Retina and Retinal Pigment Epithelium

To correlate structural changes of combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) with patient age. Retrospective study. Fifty eyes of 49 patients (age range, 1-74 years) with CHRRPE studied at 9 tertiary vitreoretinal institutions. We analyzed the clinical findings with respect to lesion topography and pigmentation as well as investigated the OCT findings regarding the thickness, vitreoretinal interface, outer plexiform layer distortion, ellipsoid zone disruption, and retinal pigment epithelium-Bruch's membrane complex involvement of CHRRPE. Clinical and imaging findings of CHRRPE at different ages. Analysis of 50 CHRRPE patients revealed that younger patients were more likely to demonstrate partial thickness involvement of the retina (P= 0.009) with predominantly inner retinal layer involvement (P=0.04). The inverse was true for older patients with CHRRPE. In addition, older patients more commonly showed pigmentary changes. Eyes with CHRRPE were more likely to show an increase in central macular thickness independently of tumor location. Based on these findings, we believe that CHRRPE typically begins in the inner retina and continues toward the outer retina over time, with increase in central macular thickness, despite the location of the tumor.

GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone–rod dystrophy but not for stationary night blindness

Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.

Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases.

Oxidative stress and inflammation play crucial roles in the development and progression of retinal diseases. Retinal damage by various etiologies can result in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). n-3 fatty acids are essential fatty acids and are necessary for homeostasis. They are important retinal membrane components and are involved in energy storage. n-3 fatty acids also have antioxidant and anti-inflammatory properties, and their suppressive effects against ROP, DR, and AMD have been previously evaluated. α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their metabolites have been shown to alleviate retinal oxidative stress and inflammation involving various biological signaling pathways. In this review, we summarize the current understanding of the n-3 fatty acids effects on the mechanisms of these retinal diseases and how they exert their therapeutic effects, focusing on ALA, EPA, DHA, and their metabolites. This knowledge may provide new remedial strategies for n-3 fatty acids in the prevention and treatment of retinal diseases associated with oxidative stress and inflammation.