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PurposeWe sought to define the role of Wwtr1 in murine ocular structure and function and determine the role of mechanotransduction in Fuchs' endothelial corneal dystrophy (FECD), with emphasis on interactions between corneal endothelial cells (CEnCs) and Descemet's membrane (DM).MethodsA Wwtr1 deficient mouse colony was established, and advanced ocular imaging, atomic force microscope (AFM), and histology/immunofluorescence were performed. Corneal endothelial wound healing was assessed using cryoinjury and phototherapeutic keratectomy in Wwtr1 deficient mice. Expression of WWTR1/TAZ was determined in the corneal endothelium from normal and FECD-affected patients; WWTR1 was screened for coding sequence variants in this FECD cohort.ResultsMice deficient in Wwtr1 had reduced CEnC density, abnormal CEnC morphology, softer DM, and thinner corneas versus wildtype controls by 2 months of age. Additionally, CEnCs had altered expression and localization of Na/K-ATPase and ZO-1. Further, Wwtr1 deficient mice had impaired CEnC wound healing. The WWTR1 transcript was highly expressed in healthy human CEnCs comparable to other genes implicated in FECD pathogenesis. Although WWTR1 mRNA expression was comparable between healthy and FECD-affected patients, WWTR1/TAZ protein concentrations were higher and localized to the nucleus surrounding guttae. No genetic associations were found in WWTR1 and FECD in a patient cohort compared to controls.ConclusionsThere are common phenotypic abnormalities seen between Wwtr1 deficient and FECD-affected patients, suggesting that Wwtr1 deficient mice could function as a murine model of late-onset FECD. Despite the lack of a genetic association between FECD and WWTR1, aberrant WWTR1/TAZ protein subcellular localization and degradation may play critical roles in the pathogenesis of FECD.

PurposeTo define the normal range of central corneal thickness (CCT) and corneal endothelial cell density (ECD) in rhesus macaques (Macaca mulatta) and the effects of age, body weight, sex, and intraocular pressure (IOP) on these parameters.MethodsOphthalmic examinations were performed on 144 rhesus macaques without anterior segment pathology. The CCT was measured via ultrasound pachymetry (USP) and specular microscopy, and the ECD was semiautomatically and manually counted using specular microscopy. Rebound tonometry was used to measure IOP. Linear regression and mixed-effects linear regression models were used to evaluate the effects of age, body weight, sex, and IOP on CCT and ECD.ResultsWe included 98 females and 46 males with an age range of 0.2 to 29.4 years. The mean CCT by USP and specular microscopy were 483 ± 39 and 463 ± 33 µm, respectively, and were statistically different (P < 0.001). The ECDs were 2717 ± 423 and 2747 ± 438 cells/mm2 by semiautomated and manual analysis, respectively. Corneal endothelial degeneration was identified in one aged rhesus macaque.ConclusionsThe mean USP and specular microscopy CCT values differed significantly, whereas the semiautomatic and manual ECD did not. The CCT was associated with the IOP and sex, whereas the ECD was associated with body weight and age (P < 0.05). As in humans, corneal disease in rhesus macaques is uncommon.Translational relevanceEstablishing reference values is fundamental to use rhesus macaques as a model for corneal disease or to identify toxicity in studies of ocular drugs or devices.

OBJECTIVE To identify genetic associations with primary glaucoma (PG) in American Cocker Spaniels using a genome-wide association study (GWAS). ANIMALS A nationwide ambidirectional case–control cohort study was performed in American Cocker Spaniels that had an ophthalmic examination performed by a veterinarian. Ninety-four dogs with PG (cases) and 111 dogs without glaucoma (controls) met phenotypic criteria and had a blood sample collected after receiving informed owner consent. PROCEDURES Genomic DNA was extracted from whole blood samples and genotyped (CanineHD BeadChip, Illumina Inc). A case–control GWAS using a linear mixed model was performed, and 3 significance thresholds were calculated (1) using a Bonferroni correction on all single nucleotide polymorphisms (SNPs) included in the GWAS, (2) using a Bonferroni correction on only the unlinked SNPs from a pruned data set, and (3) using 10,000 random phenotype permutations. RESULTS Following genotype data quality control, 89 cases and 93 controls were included in the GWAS. We identified an association on canine chromosome (CFA10); however, it did not reach statistical significance. Potential candidate genes within the surrounding linkage disequilibrium interval include coiled-coil domain containing 85A (CCDC85A) and extracellular growth factor containing fibulin extracellular matrix protein 1 (EFEMP1). CLINICAL RELEVANCE Primary glaucoma in the American Cocker Spaniel is a complex heterogeneous disease that may be influenced by a locus on CFA10. The candidate genes CCDC85A and EFEMP1 within the identified linkage disequilibrium interval have been shown to be involved in human open-angle glaucoma. [ABSTRACT FROM AUTHOR]