A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant.

Retinitis pigmentosa (RP) is a heterogenous hereditary disorder leading to blindness. Despite using next-generation sequencing technologies, causal variants in about 60% of RP cases remain unknown. The heterogeneous genetic inheritance pattern makes it difficult to pinpoint causal variants.

Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration.

Purpose: Disruption of proteostasis is a key event in many neurodegenerative diseases. Heat shock proteins (HSPs) participate in multiple functions associated with intracellular transport and proteostasis. We evaluated the effect of augmented HSP70 expression in mutant photoreceptors of mouse retinal degeneration models to test the hypothesis that failure to sustain HSP70 expression contributes to photoreceptor cell death.

Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model.

In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)121 and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. KUSs appeared to avert endoplasmic reticulum (ER) stress by maintaining ATP levels, resulting in the protection of ganglion cells from cell death.

Reduction of lipid accumulation rescues Bietti's crystalline dystrophy phenotypes.

Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a mutation and successfully established an in vitro model of BCD, i.

High-density lipoprotein mutant eye drops for the treatment of posterior eye diseases.

Age-related macular degeneration (AMD), in which choroidal neovascularization (CNV) affects the center of the retina (macula), leads to the irreversible visual loss. The intravitreal injection of anti-angiogenesis antibodies improved the prognosis of AMD, but relatively less invasive therapies should be explored. In the present study, we show that a high-density lipoprotein (HDL) mutant is a therapeutically active drug carrier capable of treating a posterior eye disease in mice via instillation.

A genome-wide association study identified a novel genetic loci STON1-GTF2A1L/LHCGR/FSHR for bilaterality of neovascular age-related macular degeneration.

Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian.

Association of Glaucoma-Susceptible Genes to Regional Circumpapillary Retinal Nerve Fiber Layer Thickness and Visual Field Defects.

Purpose: To examine the associations of the earlier reported glaucoma-related genes to the regional circumpapillary retinal nerve fiber layer thicknesses (cpRNFLTs) and corresponding visual field defects.

Methods: We studied 756 patients with primary open-angle glaucoma (POAG) and 3094 normal controls. Each participant was genotyped for nine single nucleotide polymorphisms (SNPs) of four glaucoma-susceptible genes: the CDKN2B(AS1), TMCO1, CAV1/CAV2, and SIX1/SIX6 genes.

Optical Coherence Tomography Angiography to Estimate Retinal Blood Flow in Eyes with Retinitis Pigmentosa.

Ophthalmologists sometimes face difficulties in identifying the origin of visual acuity (VA) loss in a retinitis pigmentosa (RP) patient, particularly before cataract surgery: cataract or the retinal disease state. Therefore, it is important to identify the significant factors correlating with VA. Nowadays, retinal blood flow in superficial and deep layers can be estimated non-invasively using optical coherence tomography angiography (OCTA).

Correlation of retinal arterial wall thickness with atherosclerosis predictors in type 2 diabetes without clinical retinopathy.

Aims: To evaluate retinal arterial wall thickness (WT) using high-resolution retinal imaging in patients with type 2 diabetes and assess its correlation with risk factors for arteriosclerosis.

Methods: Outer diameter, inner diameter and WT of the retinal artery were measured using adaptive optics scanning laser ophthalmoscopy in 28 patients with type 2 diabetes without clinically apparent diabetic retinopathy and normal volunteers. Laboratory values and intima-media thickness (IMT) in the common carotid artery were measured.

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors.

Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. Given that the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone-like) mouse photoreceptors.

CHOROIDAL AND RETINAL ATROPHY OF BIETTI CRYSTALLINE DYSTROPHY PATIENTS WITH CYP4V2 MUTATIONS COMPARED TO RETINITIS PIGMENTOSA PATIENTS WITH EYS MUTATIONS.

Purpose: To compare atrophy of the choroid and retina between Bietti crystalline dystrophy (BCD) patients and EYS-related retinitis pigmentosa (RP) patients with a similar degree of central visual field defects, age, and axial length (AL).

Methods: Nine eyes of nine BCD patients with CYP4V2 mutations (BCD group) were examined. Moreover, we selected 10 eyes of 10 RP patients with EYS mutations matched for age, axial length, and mean deviation (measured with the 10-2 SITA standard program; EYS-RP group), and 10 eyes of 10 normal volunteers matched for age and axial length (control group).

Screening for SLC7A14 gene mutations in patients with autosomal recessive or sporadic retinitis pigmentosa.

Purpose: In this study, we aimed to detect mutations in the SLC7A14 cationic transporter gene, which has recently been reported as a causative gene for retinitis pigmentosa (RP), in Japanese patients with autosomal recessive (AR) or sporadic RP.

Materials And Methods: We included 146 unrelated Japanese patients with AR or sporadic RP who lacked mutations in genes known to be associated with RP despite next-generation sequencing-based screening. We sequenced the seven SLC7A14 coding exons along with their flanking intronic DNA using the Sanger method.

Efficacy of Column Scatter Plots for Presenting Retinitis Pigmentosa Phenotypes in a Japanese Cohort.

Purpose: We evaluated the efficacy of column scatter plots to describe genotype-phenotype correlations in a Japanese cohort with retinitis pigmentosa (RP).

Methods: Clinical records of 121 patients with RP with identified causative mutations were reviewed. Visual acuity, central and peripheral visual fields, electroretinography (ERG), lens status, and measurements of optical coherence tomography were evaluated according to causative genes using column scatter plots.

Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies.

Purpose: To investigate the efficacy of targeted exome sequencing for mutational screening of Japanese patients with cone dystrophy (CD) or cone-rod dystrophy (CRD).

Methods: DNA samples from 43 Japanese patients with CD or CRD were sequenced using an exome-sequencing panel targeting all 193 known inherited eye disease genes and next-generation sequencing methodologies. Subsequently, candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed using distinct filtering approaches, which included the frequency of the variants in normal populations, in silico prediction tools, and cosegregation.

Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria.

Purpose: Cell death in neurodegeneration occurs at the convergence of diverse metabolic pathways. In the retina, a common underlying mechanism involves mitochondrial dysfunction since photoreceptor homeostasis and survival are highly susceptible to altered aerobic energy metabolism. We sought to develop an assay to directly measure oxygen consumption in intact retina with the goal of identifying alterations in respiration during photoreceptor dysfunction and degeneration.

Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study.

Background: Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia.

Evaluation of Photoreceptors in Bietti Crystalline Dystrophy with CYP4V2 Mutations Using Adaptive Optics Scanning Laser Ophthalmoscopy.

Purpose: To evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO).

Design: Prospective observational case series with comparison to healthy controls.

Methods: Seven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied.

Intra-familial Similarity of Wide-Field Fundus Autofluorescence in Inherited Retinal Dystrophy.

To examine the similarity of wide-field fundus autofluorescence (FAF) imaging in inherited retinal dystrophy between siblings and between parents and their children. The subjects included 17 siblings (12 with retinitis pigmentosa and 5 with cone rod dystrophy) and 10 parent-child pairs (8 with retinitis pigmentosa and 2 with cone rod dystrophy). We quantified the similarity of wide-field FAF using image processing techniques of cropping, binarization, superimposition, and subtraction.

Descriptive epidemiology of spot urine sodium-to-potassium ratio clarified close relationship with blood pressure level: the Nagahama study.

Objectives: We undertook descriptive epidemiology of spot urine sodium-to-potassium ratio (Na/K) in a population sample to clarify the close relationship between Na/K and blood pressure level independently of potential confounding factors.

Methods: Study participants consisted of 9144 apparently healthy citizens (aged 54 ± 13 years). All clinical parameters were obtained at baseline.

MMP20 and ARMS2/HTRA1 Are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is the leading cause of severe visual impairment. Despite treatment, a central scotoma often remains. The size of the scotoma depends on the lesion size of the choroidal neovascular membrane and significantly affects the patient's quality of life, and the lesion size of neovascularization also affects response to treatments.

Next-Generation Sequencing-Based Molecular Diagnosis of Choroideremia.

We screened patients with choroideremia using next-generation sequencing (NGS) and identified a novel mutation and a known mutation in the CHM gene. One patient presented an atypical fundus appearance for choroideremia. Another patient presented macular hole retinal detachment in the left eye.

Radial fundus autofluorescence in the periphery in patients with X-linked retinitis pigmentosa.

Purpose: To describe the peripheral autofluorescence images and clinical features of patients with retinal dystrophy who showed radial fundus autofluorescence (FAF) at the posterior pole.

Methods: The authors retrospectively reviewed pooled wide-field FAF images of 711 patients with retinal dystrophy and 56 family members.

Results: Eleven eyes of seven women exhibited radial FAF at the posterior pole.

The Contribution of Genetic Architecture to the 10-Year Incidence of Age-Related Macular Degeneration in the Fellow Eye.

Purpose: To correlate a genetic risk score based on age-related macular degeneration (AMD) susceptibility genes with the risk of AMD in the second eye.

Methods: This is a retrospective, open cohort study consisting of 891 unilateral AMD patients, who were followed for at least 12 months and recruited from three institutes. DNAs were genotyped using Illumina OmniExpress, HumanOmni2.