REVIEW: Current understanding of the pathogenesis of Fuchs' endothelial corneal dystrophy.

Fuchs' endothelial corneal dystrophy (FECD) is the most prominent reason for corneal-endothelial transplantations across the globe. The disease pathophysiology manifests through a combination of various genetic and non-heritable factors. This review provides a comprehensive list of known genetic players that cause FECD, and discusses the prominent pathological features that participate in disease progression, such as channel dysfunction, abnormal extracellular matrix deposition, RNA toxicity, oxidative stress, and apoptosis. Although current practices to correct visual acuity involve surgical intervention, this review also discusses the scope of various non-surgical therapeutics to remedy FECD.

rs4246215 is targeted by hsa-miR1236 to regulate FEN1 expression but is not associated with Fuchs' endothelial corneal dystrophy.

Fuchs' Endothelial Corneal Dystrophy (FECD) is a genetically complex disorder that affects individuals above 40 years of age; molecular pathogenesis of its associated genes is poorly understood. This study aims at assessing the association of flap endonuclease 1 (FEN1) polymorphisms, c.-69G>A (rs174538) and c.4150G>T (rs4246215) with FECD. Comet assay analysis reaffirmed that endogenous DNA damage was greater in FECD individuals. However, genetic analysis in 79 FECD patients and 234 unrelated control individuals prove that both the FEN1 polymorphisms, c.-69G>A (rs174538) and c.4150G>T (rs4246215), failed to show any genetic association with the FECD disease phenotype. In silico analysis and luciferase reporter assay identified 'G' allele of the 3'UTR located FEN1 polymorphism c.4150G>T as the target for binding of hsa-miR-1236-3p. This study indicates that although FEN1 polymorphisms, c.-69G>A (rs174538) and c.4150G>T (rs4246215) are not genetically associated with FECD, its transcript regulation reported in other diseases such as lung cancer which are genetically associated by rs4246215 could be mediated through miRNA, hsa-miR-1236-3p.

Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression.

Genetic variants at PTK2B-CLU locus pose as high-risk factors for many age-related disorders. However, the role of these variants in disease progression is less characterized. In this study, we aimed to investigate the functional significance of a clusterin intronic SNP, rs2279590, that has been associated with pseudoexfoliation, Alzheimer's disease (AD) and diabetes. We have previously shown that the alleles at rs2279590 differentially regulate clusterin (CLU) gene expression in lens capsule tissues. This polymorphism resides in an active regulatory region marked by H3K27Ac and DNase I hypersensitive site and is an eQTL for CLU expression. Here, we report the presence of an enhancer element in surrounding region of rs2279590. Deletion of a 115 bp intronic region flanking the rs2279590 variant through CRISPR-Cas9 genome editing in HEK293 cells demonstrated a decreased clusterin gene expression. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that rs2279590 with allele 'A' constitutes a transcription factor binding site for heat shock factor-1 (HSF1) but not with allele 'G'. By binding to allele 'A', HSF1 abrogates the enhancer effect of the locus as validated by reporter assays. Interestingly, rs2279590 locus has a widespread enhancer effect on two nearby genes, protein tyrosine kinase 2 beta (PTK2B) and epoxide hydrolase-2 (EPHX2); both of which have been previously associated with AD as risk factors. To summarize, our study unveils a mechanistic role of the common variant rs2279590 that can affect a variety of aging disorders by regulating the expression of a specific set of genes.

Genetic association of TCF4 intronic polymorphisms, CTG18.1 and rs17089887, with Fuchs' endothelial corneal dystrophy in an Indian population.

PURPOSE: To assess the genetic association of transcription factor 4 (TCF4) intronic polymorphisms and CTG18.1 allele in individuals with Fuchs' endothelial corneal dystrophy (FECD) individuals from a sample Indian population. METHODS: Forty-four FECD patients and 108 unrelated age-matched controls were recruited with informed consent for this study. Three, single nucleotide polymorphisms (SNPs) spanning the third intronic region of TCF4 (rs613872, rs17089887, and rs17089925) and an unstable trinucleotide repeat CTG18.1 allele were genotyped by direct sequencing using Sanger's method. The association of polymorphisms was analyzed using χ(2) test and logistic regression. RESULTS: SNP rs17089887 (P = 0.013) and CTG18.1 (P = 2 × 10(-4)) alleles were found to be significantly associated with FECD in the sample Indian population. However, the other two SNPs, rs613872 and rs17089925, were not likewise associated. Thirty-four percent of FECD subjects and 5% of control individuals harbor more than 50 trinucleotide repeats, which was considered as the disease threshold. CONCLUSIONS: TCF4 poses a major contributor to FECD manifestation globally, with a significant association of rs17089887 and CTG18.1 allele in the Indian population.

Artemisinin and curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity.

Deletion of tumor suppressor gene, lethal(2)giant larvae [l(2)gl], leads to brain tumor in Drosophila melanogaster at larval stage of development and severe brain dysplasia in mice. We have studied the effect of two potential antitumor drugs artemisinin and curcumin in the perspective of inhibiting l(2)gl brain tumor. Efficacies of these drugs are characterized morphologically by measuring brain sizes of untreated and treated larvae on the basis of tumor inhibition and anatomically by looking at the cellular patterning via antibody staining of the third instar Drosophila larval brains. Behavioral experiments were done in form of locomotion to correlate tumor inhibition with the revival of brain function and longevity assays to assess general health span. It was observed that both drugs show antitumor properties individually and in combination when larvae were treated with these drugs. We also found evidence for reactive oxygen species-mediated action of these drugs. Both the drugs when treated individually or together show better median life span and locomotory response. Although the efficacies of various treatments varied, overall, the positive effects of artemisinin and curcumin demonstrate a potential applicability of these drugs against brain tumor in higher organisms. It also paves a way for a simpler model system for screening such natural products for antitumor property.