EPHA2 Polymorphisms and Age-Related Cataract in India

Sundaresan, Periasamy; Ravindran, Ravilla D.; Vashist, Praveen; Shanker, A.; Nitsch, Dorothea; Talwar, Badrinath; Maraini, G; Camparini, Monica; Nonyane, Bareng A. S.; Smeeth, Liam; Chakravarthy, Usha; Hejtmancik, J. F.; Fletcher, Astrid

doi:10.1371/journal.pone.0033001

Cited by 41 publications

(30 citation statements)

References 11 publications

(18 reference statements)

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“…Thus, these mutant proteins may precipitate out and deplete wild type EPHA2 protein in the lens fiber cells, resulting in dominant deficiencies (Park et al, 2012). EPHA2 polymorphism has also been found to be associated with age-related cataracts (Jun et al, 2009; Tan et al, 2011; Sundaresan et al, 2012). In addition to the receptor EPHA2, a recent study also detected association of ephrin-A5 single nucleotide polymorphism with age-related cataracts (Lin et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin-A5−/− mice

Biswas

Son

et al. 2016

Experimental Eye Research

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Ephrin-A5, a ligand of the Eph family of receptor tyrosine kinases, plays a key role in lens fiber cell packing and cell-cell adhesion, with approximately 87% of ephrin-A5−/− mice develop nuclear cataracts. Here, we investigated the extensive formation of light-scattering globules associated with breakdown of interlocking protrusions during lens opacification in ephrin-A5−/− mice. Lenses from wild-type (WT) and ephrin-A5−/− mice between 2–21 weeks old were studied with light and electron microscopy, immunofluorescence labeling, freeze-fracture TEM and filipin cytochemistry for membrane cholesterol detection. Lens opacities with various densities were first observed in ephrin-A5−/− mice at around 60 days old. Dense cataracts in the mutant lenses were seen primarily in the nuclear region surrounded by transparent cortices from all eyes examined. We confirmed that a majority of nuclear cataracts were dislocated posteriorly and ruptured the thinner posterior lens capsule. SEM analysis indicated that numerous interlocking protrusions and wavy ridge-and-valley membrane surfaces in deep cortical and nuclear fibers did not cause lens opacity in both transparent ephrin-A5−/− and WT mice. In contrast, abundant isolated membranous globules of approximately 1,000 nm in size were distributed randomly along the intact fiber cells during early stage of all ephrin-A5−/− cataracts examined. A further examination using both SEM and TEM revealed that isolated globules were generated from the disintegrated interlocking protrusions originally located along the corners of hexagonal fiber cells. Freeze-fracture TEM further revealed the association of square-array aquaporin junctions with both isolated globules and interlocking membrane domains. This study reports for the first time that disrupted interlocking protrusions are the source of numerous large membranous globules that contribute to light scattering and nuclear cataracts in the ephrin-A5−/− mice. Our results further suggest that dissociations of N-cadherin and adherens junctions in the associated interlocking domains may result in the formation of isolated globules and nuclear opacities in the ephrin-A5−/− mice.

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Section: Discussionmentioning

confidence: 99%

Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin-A5−/− mice

Biswas

Son

et al. 2016

Experimental Eye Research

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“…In heterozygotes this protein variation results in reduced stability of the variant enzyme and mild galactokinase deficiency equivalent to about 20% of normal levels, presumably sufficient to result in cataract as an individual ages. Among others, SNPs in and near the EPH receptor A2 (EPHA2) have been associated with ARC, especially cortical (Shiels et al, 2008; Sundaresan et al, 2012), as have sequence variations in the αA-crystallin gene (CRYAA) (Bhagyalaxmi et al, 2009, 2010; Liao et al, 2014). …”

Section: Age Related Cataractmentioning

confidence: 99%

Mutations and mechanisms in congenital and age-related cataracts

Shiels

Hejtmancik

2017

Experimental Eye Research

184

138

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The crystalline lens plays an important role in the refractive vision of vertebrates by facilitating variable fine focusing of light onto the retina. Loss of lens transparency, or cataract, is a frequently acquired cause of visual impairment in adults and may also present during childhood. Genetic studies have identified mutations in over 30 causative genes for congenital or other early-onset forms of cataract as well as several gene variants associated with age-related cataract. However, the pathogenic mechanisms resulting from genetic determinants of cataract are only just beginning to be understood. Here, we briefly summarize current concepts pointing to differences in the molecular mechanisms underlying congenital and age-related forms of cataract.

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“…[46][47][48][49][50] However, only the EPHA2 association has been replicated in different populations including with cortical cataract in Caucasians and Han Chinese, with cortical cataract and PSC in Indians, and with any cataract in Caucasians and Asians from China and India. 46,[51][52][53][54] There was no association of EPHA2 variants with nuclear cataract in any population.…”

Section: Genes Associated With Age-related Cataractmentioning

confidence: 99%

Molecular Genetics of Cataract

Shiels

Hejtmancik

2014

Encyclopedia of Life Sciences

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Cataract can be defined as any opacity or cloudiness of the crystalline lens. When there is significant variation of the refractive index of the lens over distances approximating the wavelength of the transmitted light scattering occurs, resulting in opacity or cataract. Thus, transparency of the crystalline lens requires both orderly arrangement of lens cells and high density of the lens protein constituents. Breakdown of the lens micro‐architecture such as cellular disarray and vacuole formation can cause large fluctuations in optical density of the lens, with resultant cataract. Significant concentrations of high molecular weight protein aggregates of 1000 Å or more in size can also contribute to light scattering. Because 90% of soluble lens proteins is composed of lens crystallins, their short‐range ordered packing in a homogeneous phase and the homoeostatic systems that maintain their stability are critical for maintaining lens transparency. Thus, it is not surprising that approximately 44% of cataract families for whom the mutant gene is known show mutations in lens crystallins with 16% in connexins, 12% in transcription factors, 4% in intermediate filament proteins, 5% in membrane proteins, 5% in chaperones or protein degradation or proofreading proteins, and 6% in a mixed group of other genes, the remainder being unknown. Key Concepts: Cataracts are opacities of the eye lens that result from light scattering either by aggregated proteins within lens cells or disarray of the lens cells themselves. Pathogenesis of inherited cataracts serves to identify critically important developmental, metabolic and biological pathways and processes in the eye lens. Although general trends can be seen with the expression pattern of the causative gene and inherited cataract morphology, identical mutations in the same gene can cause different cataract morphologies and mutations in different genes can result in identical cataract phenotypes. In general, congenital cataracts tend to be caused by mutations that severely disrupt the gene product's structure or function and are thus inherited as highly penetrant Mendelian traits. Conversely, the underlying genetic contributors to age‐related cataracts tend to be less severe mutations that merely impair stability or function and require additional compromise by environmental or modifying genetic factors to cause opacity, so they tend to be multifactorial in their inheritance. Lens crystallins make up 90% of the soluble protein of the eye lens and are thus frequent targets for mutations that destabilise them and cause cataracts. α‐Crystallins are molecular chaperones and can bind denatured proteins, thus preventing or delaying the onset of cataracts, and especially of age‐related cataract. Many other genes implicated in cataractogenesis encode gap junction proteins, solute and aqueous transport proteins, cytoskeletal proteins, developmental transcription factors, membrane proteins, chaperones, or other proteins participating in salvage processes, all important for lens cell development and homoeostasis. In multiple instances, including GALK, EPHA2 and CRYAA, mutations resulting in dramatic destabilization of loss of activity cause congenital cataracts, whereas milder changes contribute to age‐related cataracts in the presence of additional genetic and environmental insults over time.

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EPHA2 Polymorphisms and Age-Related Cataract in India

Cited by 41 publications

References 11 publications

Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin-A5−/− mice

Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin-A5−/− mice

Mutations and mechanisms in congenital and age-related cataracts

Molecular Genetics of Cataract

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