Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial dysfunction causes serious vision loss. The only therapy for corneal haziness due to corneal endothelial diseases, including FECD, is corneal transplantation using donor corneas, and no pharmaceutical treatment is available. We provide evidence that the expression levels of transforming growth factor-β (TGF-β) isoforms and TGF-β receptors are high in the corneal endothelium of patients with FECD. A cell model based on patients with FECD shows that TGF-β signaling induced a chronic overload of ECM proteins to the endoplasmic reticulum (ER), thereby enhancing the formation of unfolded protein and triggering the intrinsic apoptotic pathway through the unfolded protein response (UPR). We propose that inhibition of TGF-β signaling may represent a novel therapeutic target that suppresses cell loss as well as the accumulation of ECM in FECD.

Citation: Okumura N, Kitahara M, Okuda H, et al. Sustained activation of the unfolded protein response induces cell death in Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci. 2017;58:3697-3707. DOI: 10.1167/iovs.16-21023 PURPOSE. The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. METHODS.Descemet's membranes with corneal endothelial cells (CECs) were obtained during keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and agrin was evaluated. Endoplasmic reticulum (ER) stress of immortalized human CECs from non-FECD subjects and from FECD patients (iHCEC and iFECD, respectively) were evaluated. The effect of MG132-mediated aggresome formation on the UPR and intrinsic pathway and the effect of mitochondrial damage on UPR were also examined. The effect of CHOP knockdown on the ER stress-mediated intrinsic pathway was also evaluated.RESULTS. Aggresome formation was higher in iFECD than in iHCEC and was colocalized with type 1 collagen, fibronectin, and agrin. GRP78, phosphorylated IRE1, PERK, and CHOP showed higher activation in iFECD than in iHCEC. MG132-mediated aggresome formation upregulated ER stress sensors, the mitochondrial membrane potential drop, cytochrome c release to the cytoplasm, and activation of caspase-9 and -3. By contrast, staurosporinemediated mitochondrial damage did not induce ER stress. Knockdown of CHOP attenuated the ER stress-induced cleavage of caspase-9, which is caused by intrinsic pathway activation.CONCLUSIONS. Excessive synthesis of extracellular matrix proteins induced unfolded protein accumulation in FECD. Prolonged ER stress-mediated cell death, occurring via the intrinsic apoptotic signaling pathway, therefore might be associated with the pathogenesis of FECD.

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PURPOSE. To examine trends in the prevalence of myopia and myopic maculopathy in a general Japanese population. METHODS. Residents of a Japanese community aged 40 years and older participated in surveys conducted in 2005, 2012, and 2017. Each participant underwent comprehensive eye examinations that included measurements of refractive error, axial lengths, and color fundus photography. Myopic maculopathy was defined according to the criteria of the Meta-analysis of Pathologic Myopia Study Group classification system. Trends in the prevalence of myopia and myopic maculopathy were tested by using a logistic regression analysis fitted by generalized estimating equations to account for individuals submitting to repeated examination. RESULTS. The age-adjusted frequencies of myopia increased significantly from 2005 to 2017 (myopia, 37.7%-45.8%; high myopia 5.8%-9.5%; all P for trend <0.001). The age-adjusted frequency of an axial length level of 26.5 mm or more increased significantly from 2005 to 2017 (3.6%-6.0%; P for trend <0.001). The age-adjusted prevalence of myopic maculopathy also increased significantly with time (1.6% in 2005, 3.0% in 2012 and 3.6% in 2017; P for trend <0.001). Upward trends were observed in the prevalence of diffuse chorioretinal atrophy and patchy chorioretinal atrophy (all P for trend <0.05). CONCLUSIONS. Our findings suggest that the prevalence of myopia and myopic maculopathy, especially diffuse chorioretinal atrophy and patchy chorioretinal atrophy, increased significantly over the past 12 years in a general Japanese population.

Purpose: To investigate single nucleotide polymorphisms (SNPs) and trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene in a large cohort of German patients with Fuchs endothelial corneal dystrophy (FECD).Methods: Genomic DNA was obtained from 398 patients with FECD and from 58 non-FECD controls. Thirty-seven previously reported SNPs were evaluated by genotyping. The 398 FECD samples were analyzed for TNR expansions by short tandem repeat (STR) assays and Southern blotting. The possible associations between TNR length and clinical parameters (age, sex, visual acuity, and central corneal thickness) were analyzed in 132 patients.