Current understanding of genetics and epigenetics in pseudoexfoliation syndrome and glaucoma.

Pseudoexfoliation is a complex, progressive, and systemic age-related disorder. The early stage of deposition of extracellular fibrillar material on ocular and extraocular tissues is termed as pseudoexfoliation syndrome (PEXS). The severe advanced stage is known as pseudoexfoliation glaucoma (PEXG), which involves increased intraocular pressure and optic nerve damage.

Role of clusterin gene 3'-UTR polymorphisms and promoter hypomethylation in the pathogenesis of pseudoexfoliation syndrome and pseudoexfoliation glaucoma.

Pseudoexfoliation (PEX) is a multifactorial age-related disease characterized by the deposition of extracellular fibrillar aggregates in the anterior ocular tissues. This study aims to identify the genetic and epigenetic contribution of clusterin (CLU) in PEX pathology. CLU is a molecular chaperone upregulated in PEX and genetically associated with the disease.

Dickkopf-1 and ROCK2 upregulation and associated protein aggregation in pseudoexfoliation syndrome and glaucoma.

Aims: The etiology of pseudoexfoliation (PEX), a stress-induced fibrillopathy and a leading cause of secondary glaucoma worldwide, remains limited. This study aims to understand the role of the Wnt antagonist Dickkopf-related protein 1 (DKK1) in PEX pathophysiology and assess its candidature as a biomarker for PEX.

Main Methods: Expression levels of DKK1 and Wnt signaling genes were assayed in the anterior ocular tissues of study subjects by qRT-PCR, Western blotting, and immunohistochemistry.

Intergenic variants, rs1200114 and rs1200108 are genetically associated along with a decreased ATP1B1 expression in Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is an age-related, bilateral corneal condition, characterized by apoptosis of the terminally differentiated endothelial cells. A genome-wide association study (GWAS) conducted in the European population in 2017, identified a new single nucleotide polymorphism (SNP), rs1200114 in the intergenic region between long intergenic non-protein coding RNA 970 (LINC00970) and ATPase Na/K transporting subunit beta 1 (ATP1B1). The major focus of the current study is to understand the genetic association of this intergenic variant, rs1200114 with FECD in the Indian population.

Wide-spread enhancer effect of SNP rs2279590 on regulating epoxide hydrolase-2 and protein tyrosine kinase 2-beta gene expression.

Polymorphisms in the PTK2B-CLU locus have been associated with various neurodegenerative disorders including pseudoexfoliation glaucoma, Alzheimer's and Parkinson's. Many of these genomic variants are within enhancer elements and modulate genes associated with the disease pathogenesis. However, mechanisms by which they control the gene expression is unknown.

Fuchs Endothelial Corneal Dystrophy associated risk variant, rs3768617 in LAMC1 shows allele specific binding of GFI1B.

Aims: To investigate the genetic and functional association of an intronic variant of LAMC1, rs3768617 with Fuchs endothelial corneal dystrophy (FECD) in the Indian population.

Methods: Blood samples were collected from age and sex matched 356 controls and 120 FECD patients after a detailed assessment via specular microscopy. Genomic DNA was extracted and genotyping was done by fluorescence based capillary electrophoresis.

Is pseudoexfoliation glaucoma a neurodegenerative disorder?

Pseudoexfoliation (PEX) is a systemic age-related progressive disorder with ocular manifestations. The earlier stage of the disease, pseudoexfoliation syndrome (PEXS) involves deposition of white fibrillar aggregates on anterior and posterior eye tissues. It is also the cause of most common form of secondary glaucoma known as pseudoexfoliation glaucoma (PEXG).

A Forward Genetic Approach to Mapping a -Element Second Site Mutation Identifies as a Novel Tumor Suppressor in .

The use of transposons to create mutations has been the cornerstone of genetics in the past few decades. Second-site mutations caused by transpositions are often devoid of transposons and thereby affect subsequent analyses. In a -element mutagenesis screen, a second site mutation was identified on chromosome 3, wherein the homozygous mutants exhibit classic hallmarks of tumor suppressor mutants, including brain tumor and lethality; hence the mutant line was initially named as [].

Epigenetic silencing of heat shock protein 70 through DNA hypermethylation in pseudoexfoliation syndrome and glaucoma.

This study is intended to investigate the epigenetic regulation of the most conserved molecular chaperone, HSP70 and its potential role in the pathophysiology of pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG), a protein aggregopathy, contributing significantly to world blindness. Expression levels of HSP70 were significantly decreased in the lens capsule (LC) of PEXS but not in PEXG compared with that in control. Bisulfite sequencing of the LC of the study subjects revealed that the CpG islands (CGIs) located in the exonic region but not in the promoter region of HSP70 displayed hypermethylation only in PEXS individuals.

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.

Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis.

Pseudoexfoliation (PEX), an ocular disorder involving deposition of proteinaceous fibrils on the surface of anterior eye tissues, is a major contributing factor to worldwide glaucoma. Excessive production and accumulation of fibrillar materials in PEX could be an indication of proteostasis imbalance. This study aims at investigating the differential expression of various genes involved in unfolded protein response and ubiquitin proteasome pathway in pseudoexfoliation (PEX) patients compared to non-PEX controls using lens capsule tissue as the study material.

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.

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.

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.

Curcumin's neuroprotective efficacy in Drosophila model of idiopathic Parkinson's disease is phase specific: implication of its therapeutic effectiveness.

Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD.

Role of an extracellular chaperone, Clusterin in the pathogenesis of Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.

Pseudoexfoliation (PEX), an age related disorder is a prominent contributor to secondary glaucoma. Earlier studies have suggested involvement of clusterin in the development of PEX. We designed a case-control study to understand the role of clusterin single nucleotide polymorphisms (SNPs) in PEX and analyzed the role of risk alleles in the disease.

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.

Impact of gene copy number variation on anesthesia in Drosophila melanogaster.

Background: Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed, but effects on sensitivity to volatile anesthetics have not been assessed in any organism.

Methods: The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which was heterozygous for a deletion of average size 400 kb.

Rab11 is essential for fertility in Drosophila.

Rab11, a small GTP binding protein involved in vesicular trafficking, has emerged as a key player in regulating various cellular events during Drosophila development and differentiation. In our earlier study a P-insertion line, Rab11mo, was established as a new hypomorphic allele of Rab11 gene, showing degenerated eye phenotype, bristle abnormalities and sterility. We show here that Rab11 is expressed in the entire testis, more prominently in the secretory cells, and in ovary it is localized at the posterior pole.

Rab11 is required during Drosophila eye development.

In an effort to identify the role of Rab11, a small GTP binding protein, during Drosophila differentiation, phenotypic manifestations associated with different alleles of Rab11 were studied. The phenotypes ranged from eye-defects, bristle abnormalities and sterility to lethality during various developmental stages. In this paper, our focus is targeted on eye defects caused by Rab11 mutations.