Search

This study aims to investigate the effect of a systemic lipopolysaccharide (LPS) stimulus in the course of laser-induced choroidal neovascularization (CNV) in C57BL/6 J mice. A group of CNV-subjected mice received 1 mg/kg LPS via the tail vein immediately after CNV induction. Mouse eyes were monitored in vivo with fluorescein angiography for 2 weeks. In situ hybridization and flow cytometry were performed in the retina at different time points. LPS led to increased fluorescein leakage 3 days after CNV, correlated with a large influx of monocyte-derived macrophages and increase of pro-inflammatory microglia/macrophages in the retina. Additionally, LPS enhanced Vegfα mRNA expression by Glul-expressing cells but not Aif1 positive microglia/macrophages in the laser lesion. These findings suggest that systemic LPS exposure has transient detrimental effects in the course of CNV through activation of microglia/macrophages to a pro-inflammatory phenotype and supports the important role of these cells in the CNV course. [ABSTRACT FROM AUTHOR]

Introduction: Mutational screening of inherited retinal disorders is prerequisite for gene targeted therapy. Our aim was to report and analyze the proportions of mutations in inherited retinal disease (IRD)-causing genes from a single center in Switzerland in order to describe the distribution of IRDs in Western Switzerland. Methods: We conducted a retrospective study of patient records. Criteria for inclusion were residence in Western Switzerland for patients and relatives presenting a clinical diagnosis of IRDs and an established molecular diagnosis managed by the genetics service of the Jules-Gonin Eye Hospital (JGEH) of Lausanne between January 2002 and December 2022. We initially investigated the IRD phenotypes in all patients (full cohort) with a clinical diagnosis, then calculated the distribution of IRD gene mutations in the entire cohort (genetically determined cohort). We analyzed a sub-group that comprised pediatric patients (≤18 years of age). In addition, we calculated the distribution of gene mutations within the most represented IRDs. Comprehensive gene screening was performed using a combined approach of different generation of DNA microarray analysis, direct sequencing, and Sanger sequencing. Results: The full cohort comprised 899 individuals from 690 families with a clinical diagnosis of IRDs. We identified 400 individuals from 285 families with an elucidated molecular diagnosis (variants in 84 genes) in the genetically determined cohort. The pediatric cohort included 89 individuals from 65 families with an elucidated molecular diagnosis. The molecular diagnosis rate for the genetically determined cohort was 58.2% (family ratio) and the 5 most frequently implicated genes per family were ABCA4 (11.6%), USH2A (7.4%), EYS (6.7%), PRPH2 (6.3%), and BEST1 (4.6%). The pediatric cohort had a family molecular diagnosis rate of 64.4% and the 5 most common mutated genes per family were RS1 (9.2%), ABCA4 (7.7%), CNGB3 (7.7%), CACNA1F (6.2%), CEP290 (4.6%). Conclusions: This study describes the genetic mutation landscape of IRDs in Western Switzerland in order to quantify their disease burden and contribute to a better orientation of the development of future gene targeted therapies. [ABSTRACT FROM AUTHOR]

Chromosomal abnormalities on the short arm of chromosome 2 in the region p11.2 have been associated with developmental delay, intellectual disability, facial anomalies, abnormal ears, skeletal and genital malformations. Here we describe a patient with a de novo interstitial heterozygous microdeletion on the short arm of chromosome 2 in the region p11.2-p12. He presents with facial dysmorphism characterized by a broad and low root of the nose and low-set protruding ears. Clinical examinations during follow-up visits revealed congenital pendular nystagmus, decreased visual acuity and psychomotor development disorder including intellectual disability. The heterozygous 5 Mb-microdeletion was characterized by an array CGH (Comparative Genomic Hybridization) analysis. In the past two decades, nine patients with microdeletions in this region have been identified by array CGH analysis and were reported in the literature. All these patients show psychomotor development disorder and outer and/or inner ear anomalies. In addition, most of the patients have mild to severe intellectual disability and show facial malformations. We reviewed the literature on PubMed and OMIM using the gene/loci names as search terms in an attempt to identify correlations between genes located within the heterozygous microdeletion and the clinical phenotype of the patient, in order to define a recognizable phenotype for the 2p11.2p12 microdeletion syndrome. We discuss additional symptoms that are not systematically present in all patients and contribute to a heterogeneous clinical presentation of this microdeletion syndrome. [ABSTRACT FROM AUTHOR]

A genome-wide single-nucleotide polymorphism (SNP) haplotype analysis is conducted to determine the causes of the recessive cone-rod dystrophies, the inherited dystrophies of the retina. The mutations in the ancient conserved domain protein 4 gene (CNNM4) are shown to widely cause the dystrophy with amelogenesis imperfecta.

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration., Introduction Retinal photoreceptor cells are highly specialized. One compartment, organized as an outer segment (OS) in vertebrates, contains a stack of over 1,000 disks harboring rhodopsin and the phototransduction machinery. [...]

The photoreceptor-specific nuclear receptor Nr2e3 is not expressed in Nr2e3rd7/rd7 mice, a mouse model of the recessively inherited retinal degeneration enhanced S-cone sensitivity syndrome (ESCS). We characterized in detail C57BL/6J Nr2e3rd7/rd7 mice in vivo by fundus photography, optical coherence tomography and fluorescein angiography and, post mortem, by histology and immunohistochemistry. White retinal spots and so-called 'rosettes' first appear at postnatal day (P) 12 in the dorsal retina and reach maximal expansion at P21. The highest density in 'rosettes' is observed within a region located between 100 and 350 µM from the optic nerve head. 'Rosettes' disappear between 9 to 12 months. Non-apoptotic cell death markers are detected during the slow photoreceptor degeneration, at a rate of an approximately 3% reduction of outer nuclear layer thickness per month, as observed from 7 to 31 months of age. In vivo analysis of Nr2e3rd7/rd7 Cx3cr1gfp/+ retinas identified microglial cells within 'rosettes' from P21 on. Subretinal macrophages were observed in vivo and by confocal microscopy earliest in 12-months-old Nr2e3rd7/rd7 retinas. At P21, S-opsin expression and the number of S-opsin expressing dorsal cones was increased. The dorso-ventral M-cone gradient was present in Nr2e3rd7/rd7 retinas, but M-opsin expression and M-opsin expressing cones were decreased. Retinal vasculature was normal. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether autofluorescence lifetime patterns within retinal pigment epithelium (RPE) atrophy differ between age-related macular degeneration (AMD) and Stargardt disease (STGD). Methods: Mean retinal autofluorescence lifetimes were measured in a short and a long spectral channel (SSC: 498–560 nm; LSC: 560–720 nm). Mean retinal fluorescence lifetimes were analyzed with corresponding clinical features, fundus images, fundus autofluorescence intensity images, and optical coherence tomography. Mean fluorescence lifetime values of atrophic areas were compared between the two cohorts and within the same patient to adjacent nonatrophic regions. Results: Mean fluorescence lifetimes within areas with RPE atrophy of 13 patients with STGD (mean age ± SEM 43.7 ± 5 years) and 30 patients with geographic atrophy (mean age: 78 ± 2 years) were analyzed and compared to age-matched healthy participants. The mean area of RPE atrophy in STGD and AMD was 6.6 ± 2.3 mm2 (range: 0.66–33.17 mm2) and 17.5 ± 3.8 mm2 (range: 0.58–50.02 mm2), respectively. In patients with AMD, atrophic areas revealed significantly longer mean fluorescence lifetime values as compared with patients with STGD (SSC: 997 ± 60 vs. 363 ± 26 ps; LSC: 880 ± 46 vs. 393 ± 23 ps; p < 0.0001). Conclusions: This study established that RPE atrophy in patients secondary to STGD and AMD display distinctive mean fluorescence lifetime characteristics. As retinal fluorescence lifetimes within areas of RPE atrophy were significantly longer in AMD patients, the analysis of specific lifetime patterns may provide additional insight into the disease processes and the pathogenetic mechanisms in the development of atrophic patches in AMD and STGD. [ABSTRACT FROM AUTHOR]