The Molecular Basis of Fuchs' Endothelial Corneal Dystrophy.

Fuchs' endothelial corneal dystrophy (FECD) is a common disease resulting from corneal endothelial cell dysfunction. It is inherited in an autosomal dominant fashion with incomplete penetrance, and with a female bias. Approximately half of cases occur sporadically, and the remainder are familial. Early and late-onset forms of the disease exist. A review of the literature has revealed more than 15 genes harbouring mutations and/or single nucleotide polymorphisms associated with FECD. The proteins encoded by these genes cover a wide range of endothelial function, including transcription regulation, DNA repair, mitochondrial DNA mutations, targeting of proteins to the cell membrane, deglutamylation of proteins, extracellular matrix secretion, formation of cell-cell and cell-extracellular matrix junctions, water pump, and apoptosis. These genetic variations will form the platform for the further understanding of the pathological basis of the disease, and the development of targeted treatments. This review aims to summarise known genetic variations associated with FECD, discuss any known molecular effects of the variations, how these provide opportunities for targeted therapies, and what therapies are currently in development.

Etiological mechanism of iridocorneal endothelial (ICE) syndrome may involve infection of herpes simplex virus (HSV) and integration of viral genes into human genome.

Iridocorneal (ICE) syndrome is a rare ocular disease characterized by abnormal proliferation of corneal endothelial cells, progressive obstruction of irido-corneal angle and atrophy of iris. ICE syndrome progressed slowly, but can cause serious complications such as secondary glaucoma in late stage. Because the etiology of ICE syndrome is not clear, there is still no effective treatment in clinical practice. Previous studies have detected herpes simplex virus (HSV) DNA inside patient's aqueous humor. However, no further explanation for HSV-related etiology of ICE syndrome was established. Besides, construction of animal models using HSV all failed, leaving behind a blank space about how HSV infection finally led to ICE syndrome. By summarizing findings from previous studies, we came up with a hypothesis about etiology of ICE syndrome: HSV infection initiated ICE syndrome by integration of viral genetic material into human genome. Infection of HSV changed activity and morphology of endothelial cells, making them regain the ability of mitosis. Proof of such hypothesis will provide a theoretical foundation for construction of animal models and effective intervention of the disease.

Mitochondrial A3243G mutation results in corneal endothelial polymegathism.

PURPOSE: The mitochondrial DNA point mutation A3243G leads to a spectrum of syndromes ranging from MIDD to MELAS. Ocular manifestations include pattern macular dystrophy and concentric perifoveal atrophy. Given the high metabolic demand of corneal endothelial cells, we performed specular biomicroscopy analysis in patients harboring the mitochondrial DNA point mutation A3243G to assess for the associated presence of corneal endothelial abnormalities. METHODS: We present a case series with participants from two institutions. Patients diagnosed with macular dystrophy associated with MIDD or MELAS, and the mitochondrial DNA point mutation A3243G were recruited. Exclusion criteria included a prior diagnosis, or a positive family history, of endothelial corneal dystrophy. Slit-lamp corneal examination and specular biomicroscopy were performed. Corneal endothelial cell count, cell size and polymegathism, and central corneal thickness were assessed. Patients diagnosed with MIDD or MELAS based on clinical history and examination were genetically tested for the mitochondrial DNA point mutation A3243G using pyrosequencing. RESULTS: Five patients (two male and three female participants) from five different families, and with different ethnic backgrounds, met the inclusion criteria. Their ages ranged from 41 to 60 years. Corneal endothelial changes observed using slit-lamp examination were primarily mild to rare guttata. Specular biomicroscopy displayed mainly polymegathism associated with guttata. The average endothelial cell count was 2358 ± 456 cells per mm2, the average endothelial cell size was 442 ± 103 µm2 and the average central corneal thickness (CCT) was 551 ± 33 µm. These values were similar to that of the average population. The average coefficient of variation (COV), an index of heterogeneity in cell size, was 42.0 ± 4.1%. When compared to the average population, the average COV was significantly higher than predicted for the patients' age. None of the patients had signs of corneal edema. One patient had a pre-Descemet's opacity. CONCLUSIONS: In patients with the mitochondrial DNA point mutation A3243G, corneal endothelial polymegathism is present. This is mainly associated with mild guttata. The findings of corneal endothelial cell polymegathism may be a biomarker of mitochondrial disease, specifically in patients with the mitochondrial DNA A3243G mutation.

The emerging roles of TCF4 in disease and development.

Genome-wide association studies have identified common variants in transcription factor 4 (TCF4) as susceptibility loci for schizophrenia, Fuchs' endothelial corneal dystrophy, and primary sclerosing cholangitis. By contrast, rare TCF4 mutations cause Pitt-Hopkins syndrome, a disorder characterized by intellectual disability and developmental delay, and have also been described in patients with other neurodevelopmental disorders. TCF4 therefore sits at the nexus between common and rare disorders. TCF4 interacts with other basic helix-loop-helix proteins, forming transcriptional networks that regulate the differentiation of several distinct cell types. Here, we review the role of TCF4 in these seemingly diverse disorders and discuss recent data implicating TCF4 as an important regulator of neurodevelopment and epithelial-mesenchymal transition.

[Gene therapy in ophthalmology: state of the art]. / Gentherapie in der Ophthalmologie: Stand der Forschung.

The term "gene therapy" denotes the treatment of diseases or gene deficiencies by introduction of genes into cells. To achieve this goal, vectors are used to transfer the genetic information into the cells. Thus, the protein of interest can be overexpressed or silenced. On account of its easy accessibility, the good compartmentalisation and the separation from the main bloodstream by the blood-retina barrier, the eye represents a very attractive target to treat ocular diseases by gene therapy. In this work, we provide an overview of the progress in ocular gene therapy over the last decade and give an outlook on future developments.

[Glaucoma with primary iris malformations. Axenfeld-Rieger syndromes, ICE syndromes (essential iris atrophy, Chandler's syndrome, Cogan-Reese syndrome), aniridia]. / Glaukome bei primären Irisveränderungen. Axenfeld-Rieger-Syndrome, ICE-Syndrome (essenzielle Irisatrophie, Chandler-Syndrom, Cogan-Reese-Syndrom), Aniridie.

Iris malformations are often associated with malformations of the entire eye and systemic diseases. Malformations of the anterior chamber angle can lead to juvenile glaucoma. Axenfeld-Rieger syndromes have autosomal dominant transmission and are associated with juvenile glaucoma in 50-60% of patients. Besides eye anomalies craniofacial malformations are also typical. The etiology of iridocorneal endothelial (ICE) syndrome is unclear but atypical endothelial cells lead to malformations of the entire anterior eye segment of the eye and glaucoma. Aniridia is a bilateral, congenital malformation which manifests sporadically and transmission is usually autosomal dominant. Glaucoma, malformations of the entire eye and systemic malformations are associated with aniridia. Conservative and microsurgical treatment of glaucoma of these syndromes need the cooperation of different medical subspecialties and are often ineffective.