Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of the cytoskeleton in lens was first considered when cytoplasmic microtubules were observed in elongating fibre cells of the chick lens nearly 40 years ago. Since that time, tubulin, actin, vimentin and intermediate filaments have been identified and found to function in mitosis, motility and cellular morphology during lens cell differentiation. A role for the cytoskeleton in accommodation has been proposed and modification of the cytoskeletal proteins has been observed in several cataract models. Recently, a progressive increase in protein aggregation and lens opacification was found to correspond with the loss of cytoskeletal protein in the selenite model for cataract. In the present report a model is proposed for the role of tubulin, actin, vimentin, spectrin and the lens-specific filaments, filensin and CP49, in the establishment and maintenance of transparent lens cell structure.
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PMID:Lens cytoskeleton and transparency: a model. 1062 19

Purpose: Approximately 50% of congenital and childhood cataracts seen in the clinic is of undetermined origin. Biochemical analysis of the cataracts is rare. This study analyzes lens proteins to determine the mechanism of congenital and childhood cataracts. Method: We analyzed the lens proteins from 10 young patients after cataract operations, using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), densitometry analysis, and Western immunoblotting.Results: Densitometry of separated proteins showed a decrease in the high molecular protein bands of posterior subcapsular cataract (PSC). Specifically, spectrin (235 kDa), filensin (100 kDa), and vimentin (57 kDa) were absent from the SDS-PAGE of PSC. Increases in filensin and vimentin were observed in a Christmas tree cataract and lamellar cataracts. Western immunoblots confirmed the densitometry of SDS-PAGE.Conclusion: These results suggest that changes in cytoskeletal proteins may contribute to congenital and childhood cataracts.
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PMID:Changes in cytoskeletal proteins in childhood cataract lenses 1071 92

The retinoblastoma tumor suppressor, Rb, is a transcription cofactor that controls cell proliferation, survival and differentiation. Mutant mouse embryos lacking Rb exhibit ectopic proliferation and apoptosis that are mediated in some tissues by E2F1, a major partner of Rb, and by the p53 tumor suppressor. Whether E2F1 and p53 also mediate the differentiation defects in Rb mutant embryos is, however, not clear. Here we show that partially rescued mgRb:Rb-/- mutant fetuses exhibit ectopic lens epithelial cell proliferation, apoptosis and severe cataract. The abnormal cell proliferation and apoptosis were significantly suppressed in the lens of compound mutant fetuses lacking both Rb and E2F1 at embryonic day (E) E15.5. Interestingly however, at E18.5, only ectopic proliferation, not apoptosis, was dramatically reduced in mgRb:Rb-/-:E2F1-/- lenses. In contrast, p53 did not exert such a stage-specific effect and apoptosis was invariably suppressed in mgRb:Rb-/-:p53-/- composite mutant lenses throughout embryogenesis. Using RT-PCR and in situ hybridization analyses, we identified a subset of lens specific genes, most notably the late differentiation marker filensin, which were not properly induced during lens development in mgRb:Rb-/-fetuses. Remarkably, despite the inhibition of cell proliferation and apoptosis, the degeneration of lens fibers and aberrant expression of filensin were only marginally corrected in mgRb:Rb-/-:E2F1-/- fetuses at E15.5 but not at all at E18.5 or in mgRb:Rb-/-:p53-/mutant fetuses. Thus, inactivation of E2F1 reduces ectopic cell proliferation and stage-specific p53-dependent apoptosis but does not rescue the differentiation defects associated with loss of Rb during lens development.
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PMID:E2F1 mediates ectopic proliferation and stage-specific p53-dependent apoptosis but not aberrant differentiation in the ocular lens of Rb deficient fetuses. 1114 59

Several families of growth factors have been identified as regulators of cell fate in the developing lens. Members of the fibroblast growth factor family are potent inducers of lens fiber differentiation. Members of the transforming growth factor beta (TGFbeta) family, particularly bone morphogenetic proteins, have also been implicated in various stages of lens and ocular development, including lens induction and lens placode formation. However, at later stages of lens development, TGFbeta family members have been shown to induce pathological changes in lens epithelial cells similar to those seen in forms of human subcapsular cataract. Previous studies have shown that type I and type II TGFbeta receptors, in addition to being expressed in the epithelium, are also expressed in patterns consistent with a role in lens fiber differentiation. In this study we have investigated the consequences of disrupting TGFbeta signaling during lens fiber differentiation by using the mouse alphaA-crystallin promoter to overexpress mutant (kinase deficient), dominant-negative forms of either type I or type II TGFbeta receptors in the lens fibers of transgenic mice. Mice expressing these transgenes had pronounced bilateral nuclear cataracts. The phenotype was characterized by attenuated lens fiber elongation in the cortex and disruption of fiber differentiation, culminating in fiber cell apoptosis and degeneration in the lens nucleus. Inhibition of TGFbeta signaling resulted in altered expression patterns of the fiber-specific proteins, alpha-crystallin, filensin, phakinin and MIP. In addition, in an in vitro assay of cell migration, explanted lens cells from transgenic mice showed impaired migration on laminin and a lack of actin filament assembly, compared with cells from wild-type mice. These results indicate that TGFbeta signaling is a key event during fiber differentiation and is required for completion of terminal differentiation.
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PMID:Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation. 1164 Dec 23

Buthionine sulfoximine (BSO), a specific inhibitor of glutathione biosynthesis, induces oxidative cataracts following multiple injections into mice at 1 week of age. Cultures of lenses with (35)S-methionine have previously demonstrated altered patterns of protein biosynthesis that precede and accompany these cataracts. To obtain parallel information about changes in protein phosphorylation during cataract development, lenses from BSO-treated or control mouse pups were cultured for 3 hr at 37 degrees C with (32)P(i), homogenized in phosphate buffer, and resolved by centrifugation into water-soluble (WS) and water-insoluble (WI) fractions. These were characterized by 2D-gel electrophoresis, Coomassie blue staining, phosphorimaging, immunoblotting, and tandem mass spectrometry. Heaviest labelling was in the WI fraction. The labelled 2D-gel spots included: (1) a series of phosphorylated filensins at 95 kDa; (2) a major radioactive spot at 45-50 kDa, slightly anodic to actin and the beaded filament protein, phakinin (CP 49); (3) a phosphorylated betaB1-crystallin, considerably anodic to parent betaB1; (4) an acidic cluster of labelled alphaA-crystallins, phosphorylated in part at serine-148, and (5) a labelled trace alpha crystallin, slightly anodic to alphaB-crystallin. The results confirm previously reported phosphorylations of actin, phakinin, alphaA- and alphaB-crystallin, demonstrate previously unrecognized phosphorylations of filensin and betaB1-crystallin, and provide unequivocal evidence for phosphorylation of alphaA-crystallin at serine-148. The earliest changes in phosphorylation detected after BSO treatment were increased labelling of alphaA- and alphaB-crystallin during cataract stages 1-3, coupled with a general decrease in protein labelling. In stage 5 cataracts, phosphorylated alpha crystallins persisted as the dominant labelled species. However, the major modifications of alphaA-crystallin in advanced BSO cataracts were unlabelled and partially degraded, in contrast to phosphorylated alphaA. It is therefore proposed that phosphorylation of alphaA-crystallin may confer resistance to proteolytic degradation.
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PMID:Altered patterns of phosphorylation in cultured mouse lenses during development of buthionine sulfoximine cataracts. 1238 96

Mammalian ocular lens development results via a differentiation program that is highly regulated by tissue-specific transcription factors. Central to this is the terminal differentiation of fiber cells, which develop from epithelial cells on the anterior surface of the lens, accompanied by a change in cell shape and expression of structural proteins (such as membrane proteins MP19, MIP26, connexin 43, 46, and 50, cytoskeletal proteins CP49, CP115, and alpha, beta, and gamma crystallins), creating a transparent, refractive index gradient in the lens. Mutations in genes controlling eye development and in lens structural protein genes are associated with multiple ocular developmental disorders, including cataracts and other opacities of the lens. Here we show that heat shock transcription factor 4 (HSF4) expression in the developing lens is required for correct lens development and that inactivation of hsf4 leads to early postnatal cataract formation with primary effects specific to terminal fiber cell differentiation. These data suggest that HSF4 acts as a critical transcription factor for lens-specific target gene expression, in particular regulating the small 25 kDa heat shock protein that acts as a modifier for lens opacity and cataract development. Thus, HSF4 fulfills a central role in controlling spatial and temporal expression of genes critical for correct development and function of the lens.
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PMID:Unique contribution of heat shock transcription factor 4 in ocular lens development and fiber cell differentiation. 1559 27

Beaded filaments are the major cytoskeletal element of the eye lens and they are essential to the optical properties of the eye lens. They were discovered in 1972 by Harry Maisel and Margaret Perry and have since been found to comprise two novel intermediate filament proteins, CP49 and filensin. These proteins possess unique structure features and unusual assembly characteristics, which distinguish them from canonical IF proteins. Whilst CP49 is completely tailless, filensin has a rather short rod domain and extremely large C-terminal tail domain. In vitro, CP49 and filensin do not form IFs on their own. In vitro studies suggest that CP49 and filensin have a distinct coassembly mechanism. Whilst CP49 self-assembles into thick bundles of filaments, filensin only forms short fibrils, but when combined together they form filaments. The generation of gene knockouts by the targeted deletion of Bfsp1 and Bfsp2 that encode filensin and CP49, respectively, have been made to explore the function of beaded filaments in the lens. Our results suggest that the lens-specific beaded filaments are the key cytoskeletal element in organising and maintaining lens fibre cell architecture and are a key factor in determining the optical properties of the lens. We have also found that some common mouse strains contain a natural mutation in Bfsp2 that will effectively generate a CP49 knockout. This finding has important implications for lens research involving other gene knockouts maintained on a 129 background. It has also been observed that mutations in Bfsp2 are the genetic basis of inherited human cataract. Collectively, these data demonstrate that beaded filaments are fundamental to lens function.
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PMID:Seeing is believing! The optical properties of the eye lens are dependent upon a functional intermediate filament cytoskeleton. 1577 82

Cataract is a dynamical process of lens opacity formation involving many inter- and intracellular regulations, as well as metabolic genes and transcription factors. Using a series of microarray-derived mRNA profiles for human cataractogenesis (Hawse et al. Mol. Vision 2003, 9, 515-537), we develop a promoter-based system-theoretic modeling to demonstrate model-driven prediction of gene expression levels and to identify the role of critical cis-acting elements. In this study, 14 key mRNA expression data from the structural and pathological molecules of age-related cataract samples are used. The first seven genes consist of structural molecules, and the second half of genes are composed of heat shock proteins, filensin, and glutathione peroxidase 3. The presented result demonstrates that mRNA expression levels of structural proteins such as crystallins can be successfully predicted from 5' flanking regulatory DNA sequences. In addition, predicted gene expression levels of heat shock protein, beta-tubulin, and alphaA-crystallin accurately estimate the stimulatory or inhibitory role of distributed cis-acting elements, i.e., c-Myc, GATA-1, GR, NE-E, and Pit-1. Although it is difficult to predict the overall gene expression levels in cataract samples, the present study shows the potential use of promoter-based modeling and prediction of the gene expression levels for age-related cataract.
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PMID:Prediction of gene expression levels and the role of cis-acting elements in age-related cataract by applying a promoter-based modeling approach. 1608 Jun 80

The glass-like transparency of the human eye lens is achieved by the tight packing of abundant crystallin proteins. However, the precise role of the accessory non-crystallin proteins is not well understood. We have carried out 2-DE mapping of these proteins in rat lens. This showed the presence of the high molecular weight filamentous structural proteins spectrin, filensin, tubulin, vimentin, actin and phakinin as well as several forms of potential crystallin oligomers comprised of alphaA, betaB1, betaA1 and betaA4 chains. Other proteins that were present include, heat shock protein 71, WD repeat protein 1, and several enzymes including alpha-enolase, pyruvate kinase, transketolase and aldose reductase. 2-D-DIGE analysis revealed several expression differences between the lens proteomes of male and female rats. Female rat lenses contained lower levels of aldose reductase, increased proteolyic fragments of the structural proteins filensin, vimentin and phakinin and higher levels of potential alphaA, betaB1 and betaA1 crystallin oligomers. Taken together these findings suggest that there are potential differences in oxidative stress regulation between male and female rat lenses, which may have implications on susceptibility to cataract formation. Future studies aimed at elucidating pre-cataractic changes in the non-crystallin proteins described here may facilitate identification of novel markers involved in cataractogenesis.
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PMID:Detection of gender differences in rat lens proteins using 2-D-DIGE. 1634 38

Filensin (BFSP1) and CP49 (BFSP2) represent two members of the IF protein superfamily that are thus far exclusively expressed in the eye lens. Mutations in both proteins cause lens cataract and careful consideration of the detail of these cataract phenotypes alerts us to several interesting features concerning the function of filensin (BFSP1) and CP49 (BFSP2) in the lens. With the first filensin (BFSP1) mutation now having been reported to cause a recessive cataract phenotype, there is the suggestion that the mutation could predispose heterozygote carriers to the early onset of age-related nuclear cataract. In the case of CP49 (BFSP2), there are now three unrelated families who have been identified with a common E233 Delta mutation. Very interestingly this is linked to myopia in one family. Despite the apparent phenotypic differences of the filensin (BFSP1) and CP49 (BFSP2) mutations, the data are still consistent with the beaded filament proteins being essential for lens function and specifically contributing to the optical properties of the lens. The fact that none of the mutations thus far reported affect either the conserved LNDR or TYRKLLEGE motifs that flank the central rod domain supports the view that this pair of IF proteins have unusual structural features and a distinctive assembly mechanism. The multiple sequence divergences suggest these proteins have been adapted to the specific functional requirements of lens fibre cells, a function that can be traced from squid to man.
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PMID:Insights into the beaded filament of the eye lens. 1749 Jun 42


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