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)

Immunocytochemistry of eye lens cells from transgenic mice coexpressing desmin and vimentin reveals that the transgenic desmin expression is not uniform. In the same lens, some epithelial and fiber cells overexpress desmin, while in others the desmin gene seems to be silent. Conversely, the endogenous vimentin is always expressed. The concomitant expression of vimentin and desmin results in the assembly of hybrid intermediate filaments (IFs). Moreover, the overexpression of the transgene generates pleomorphic IF assembly and leads to intermingled filamentous whorls and to accumulation of amorphous desmin. The abnormalities of IF assembly induced by the genetic manipulation are correlated with perturbation of the enucleation process in the lens fibers, changes in cell shape, fiber fusion and extensive internalization of the general plasma membrane and junctional domains. The alterations of lens cells described in this study were observed in all transgenic mice examined. The level of expression of the transgene was paralleled by the degree of damage. Our results indicate that proper expression, assembly and membrane interaction of IFs play an important role in the terminal differentiation of the lenticular epithelium into fiber cells. We anticipate that alterations during these processes may initiate cataract formation.
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PMID:Plasma membrane-cytoskeleton damage in eye lenses of transgenic mice expressing desmin. 207 9

We describe the light microscopic, immunohistochemical, and electron microscopic findings in a sporadic case of congenital microcoria in a 72-year-old man with senile cataract. We demonstrated a lack of myofilaments and desmin in the stromal cytoplasmic processes of the anterior pigmented cells of the iris, although other features of muscle differentiation were present in these few surviving cell processes that normally form the pupil dilator muscle. Degenerative changes in anterior pigment cells and iris stromal atrophy were thought to be late secondary features of microcoria. The findings suggest that congenital microcoria results from a defect of intermediate filaments in the terminal fetal stages of differentiation of the anterior pigmented epithelial cell of the iris, with absence of myofilaments and consequent failure of development of a functional dilator pupil muscle.
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PMID:The ultrastructural pathological features of congenital microcoria. A case report. 291 Feb 94

The cytoskeleton, of which the main components in the human eye are actin microfilaments, intermediate filaments and microtubules with their associated proteins, is essential for the normal growth, maturation, differentiation, integrity and function of its cells. These components interact with intra- and extracellular environment and each other, and their profile frequently changes during development, according to physiologic demands, and in various diseases. The ocular cytoskeleton is unique in many ways. A special pair of cytokeratins, CK 3 and 12, has apparently evolved only for the purposes of the corneal epithelium. However, other cytokeratins such as CK 4, 5, 14, and 19 are also important for the normal ocular surface epithelia, and other types may be acquired in keratinizing diseases. The intraocular tissues, which have a relatively simple cytoskeleton consisting mainly of vimentin and simple epithelial CK 8 and 18, differ in many details from extraocular ones. The iris and lens epithelium characteristically lack cytokeratins in adults, and the intraocular muscles all have a cytoskeletal profile of their own. The dilator of the iris contains vimentin, desmin and cytokeratins, being an example of triple intermediate filament expression, but the ciliary muscle lacks cytokeratin and the sphincter of the iris is devoid even of vimentin. Conversion from extraocular-type cytoskeletal profile occurs during fetal life. It seems that posttranslational modification of cytokeratins in the eye may also differ from that of extraocular tissues. So far, it has not been possible to reconcile the cytoskeletal profile of intraocular tissues with their specific functional demands, but many theories have been put forward. Systematic search for cytoskeletal elements has also revealed novel cell populations in the human eye. These include transitional cells of the cornea that may represent stem cells on migration, myofibroblasts of the scleral spur and juxtacanalicular tissue that may modulate aqueous outflow, and subepithelial matrix cells of the ciliary body and myofibroblasts of the choroid that may both participate in accommodation. In contrast to the structure and development of the ocular cytoskeleton, changes that take place in ocular disease have not been analysed systematically. Nevertheless, potentially meaningful changes have already been observed in corneal dystrophies (Meesmann's dystrophy, posterior polymorphous dystrophy and iridocorneal endothelial syndrome), degenerations (pterygium) and inflammatory diseases (Pseudomonas keratitis), in opacification of the lens (anterior subcapsular and secondary cataract), in diseases characterized by proliferation of the retinal pigment epithelium (macular degeneration and proliferative vitreoretinopathy), and in intraocular tumours (uveal melanoma). In particular, upregulation of alpha-smooth muscle actin seems to be a relatively general response typical of spreading and migrating corneal stromal and lens epithelial cells, trabecular cells and retinal pigment epithelial cells.
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PMID:Structure, development and function of cytoskeletal elements in non-neuronal cells of the human eye. 969 98

A point mutation of a highly conserved arginine residue in alphaA and alphaB crystallins was shown to cause autosomal dominant congenital cataract and desmin-related myopathy, respectively, in humans. To study the structural and functional consequences of this mutation, human alphaA and alphaB crystallin genes were cloned and the conserved arginine residue (Arg-116 in alphaA crystallin and Arg-120 in alphaB crystallin) mutated to Cys and Gly, respectively, by site-directed mutagenesis. The recombinant wild-type and mutant proteins were expressed in Escherichia coli and purified. The mutant and wild-type proteins were characterized by SDS-polyacrylamide gel electrophoresis, Western immunoblotting, gel permeation chromatography, fluorescence, and circular dichroism spectroscopy. Biophysical studies reveal significant differences between the wild-type and mutant proteins. The chaperone-like activity was studied by analyzing the ability of the recombinant proteins to prevent dithiothreitol-induced aggregation of insulin. The mutations R116C in alphaA crystallin and R120G in alphaB crystallin reduce the chaperone-like activity of these proteins significantly. Near UV circular dichroism and intrinsic fluorescence spectra indicate a change in tertiary structure of the mutants. Far UV circular dichroism spectra suggest altered packing of the secondary structural elements. Gel permeation chromatography reveals polydispersity for both of the mutant proteins. An appreciable increase in the molecular mass of the mutant alphaA crystallin is also observed. However, the change in oligomer size of the alphaB mutant is less significant. These results suggest that the conserved arginine of the alpha-crystallin domain of the small heat shock proteins is essential for their structural integrity and subsequent in vivo function.
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PMID:Structural and functional consequences of the mutation of a conserved arginine residue in alphaA and alphaB crystallins. 1044 86

alpha-Crystallin is the principal lens protein which, in addition to its structural role, also acts as a molecular chaperone, to prevent aggregation and precipitation of other lens proteins. One of its two subunits, alphaB-crystallin, is also expressed in many nonlenticular tissues, and a natural missense mutation, R120G, has been associated with cataract and desmin-related myopathy, a disorder of skeletal muscles [Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D & Fardeau M (1998) Nat Genet20, 92-95]. In the present study, real-time 1H-NMR spectroscopy showed that the ability of R120G alphaB-crystallin to stabilize the partially folded, molten globule state of alpha-lactalbumin was significantly reduced in comparison with wild-type alphaB-crystallin. The mutant showed enhanced interaction with, and promoted unfolding of, reduced alpha-lactalbumin, but showed limited chaperone activity for other target proteins. Using NMR spectroscopy, gel electrophoresis, and MS, we observed that, unlike the wild-type protein, R120G alphaB-crystallin is intrinsically unstable in solution, with unfolding of the protein over time leading to aggregation and progressive truncation from the C-terminus. Light scattering, MS, and size-exclusion chromatography data indicated that R120G alphaB-crystallin exists as a larger oligomer than wild-type alphaB-crystallin, and its size increases with time. It is likely that removal of the positive charge from R120 of alphaB-crystallin causes partial unfolding, increased exposure of hydrophobic regions, and enhances its susceptibility to proteolysis, thus reducing its solubility and promoting its aggregation and complexation with other proteins. These characteristics may explain the involvement of R120G alphaB-crystallin with human disease states.
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PMID:R120G alphaB-crystallin promotes the unfolding of reduced alpha-lactalbumin and is inherently unstable. 1567 Jan 52

The vertebrate lens has a distinct polarity and structure that are regulated by growth factors resident in the ocular media. Fibroblast growth factors, in concert with other growth factors, are key regulators of lens fiber cell differentiation. While members of the transforming growth factor (TGFbeta) superfamily have also been implicated to play a role in lens fiber differentiation, inappropriate TGFbeta signaling in the anterior lens epithelial cells results in an epithelial-mesenchymal transition (EMT) that bears morphological and molecular resemblance to forms of human cataract, including anterior subcapsular (ASC) and posterior capsule opacification (PCO; also known as secondary cataract or after-cataract), which occurs after cataract surgery. Numerous in vitro and in vivo studies indicate that this TGFbeta-induced EMT is part of a wound healing response in lens epithelial cells and is characterized by induced expression of numerous extracellular matrix proteins (laminin, collagens I, III, tenascin, fibronectin, proteoglycans), intermediate filaments (desmin, alpha-smooth muscle actin) and various integrins (alpha2, alpha5, alpha7B), as well as the loss of epithelial genes [Pax6, Cx43, CP49, alpha-crystallin, E-cadherin, zonula occludens-1 protein (ZO-1)]. The signaling pathways involved in initiating the EMT seem to primarily involve the Smad-dependent pathway, whereby TGFbeta binding to specific high affinity cell surface receptors activates the receptor-Smad/Smad4 complex. Recent studies implicate other factors [such as fibroblast growth factor (FGFs), hepatocyte growth factor, integrins], present in the lens and ocular environment, in the pathogenesis of ASC and PCO. For example, FGF signaling can augment many of the effects of TGFbeta, and integrin signaling, possibly via ILK, appears to mediate some of the morphological features of EMT initiated by TGFbeta. Increasing attention is now being directed at the network of signaling pathways that effect the EMT in lens epithelial cells, with the aim of identifying potential therapeutic targets to inhibit cataract, particularly PCO, which remains a significant clinical problem in ophthalmology.
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PMID:Transforming growth factor-beta-induced epithelial-mesenchymal transition in the lens: a model for cataract formation. 1594 92

Small heat shock proteins (sHSPs) function as molecular chaperones, preventing stress induced aggregation of partially denatured proteins and promoting their return to native conformations when favorable conditions pertain. Sequence similarity between sHSPs resides predominately in an internal stretch of residues termed the alpha-crystallin domain, a region usually flanked by two extensions. The poorly conserved N-terminal extension influences oligomer construction and chaperone activity, whereas the flexible C-terminal extension stabilizes quaternary structure and enhances protein/substrate complex solubility. sHSP polypeptides assemble into dynamic oligomers which undergo subunit exchange and they bind a wide range of cellular substrates. As molecular chaperones, the sHSPs protect protein structure and activity, thereby preventing disease, but they may contribute to cell malfunction when perturbed. For example, sHSPs prevent cataract in the mammalian lens and guard against ischemic and reperfusion injury due to heart attack and stroke. On the other hand, mutated sHSPs are implicated in diseases such as desmin-related myopathy and they have an uncertain relationship to neurological disorders including Parkinson's and Alzheimer's disease. This review explores the involvement of sHSPs in disease and their potential for therapeutic intervention.
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PMID:The small heat shock proteins and their role in human disease. 1594 97

Myofibrillar myopathies are genetically heterogeneous. We present a sporadic case of an 8-year-old boy with unusual combination of congenital skeletal muscle myopathy, cataract and poly/syndactyly. Muscle pathology revealed a mild myopathic picture with hyaline plaques, showing dark green staining in modified trichrome reaction, and strong immunoreactivity for alphaB-crystallin, desmin and dystrophin. Analysis of the coding sequences of the desmin, alphaB-crystallin, SEPN1, lamin A/C genes and of exon 2 of the myotilin gene showed no abnormalities in the patient. Presented case expands the wide clinical spectrum of myofibrillar myopathies, reinforcing the need for further exploration of genetic causes for this group of disorders.
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PMID:Myofibrillar myopathy with congenital cataract and skeletal anomalies without mutations in the desmin, alphaB-crystallin, myotilin, LMNA or SEPN1 genes. 1700 1

Small heat shock proteins (sHsps) belong to molecular chaperones, which protect prokaryotic and eukaryotic cells against deleterious effects, of stress. sHsps prevent stress induced, irreversible aggregation of damaged proteins and facilitate renaturation of bound substrates cooperating with other molecular chaperones. This review summarizes recent studies focused mainly on the involvement of sHsps in diseases related to protein aggregation. sHsps are often a component of protein aggregates forming during progress of neurodegenerative disorders. Mutation in sHsps genes have been identified, which are responsible for development of cataract, desmin related myopathy and neuropathies. sHsps protect cells against oxidative stress resulting from ischemia/reperfusion during heart or brain stroke. Several studies indicate that sHsp participate in regulation of apoptosis and are involved in cancerogenesis. Uncovering the sHsps role in diseases enable to develop new therapeutic strategies.
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PMID:[Small heat shock proteins--role in apoptosis, cancerogenesis and diseases associated with protein aggregation]. 1771 84

Vimentin is the main intermediate filament (IF) protein of mesenchymal cells and tissues. Unlike other IF-/- mice, vimentin-/- mice provided no evidence of an involvement of vimentin in the development of a specific disease. Therefore, we generated two transgenic mouse lines, one with a (R113C) point mutation in the IF-consensus motif in coil1A and one with the complete deletion of coil 2B of the rod domain. In epidermal keratins and desmin, point mutations in these parts of the alpha-helical rod domain cause keratinopathies and desminopathies, respectively. Here, we demonstrate that substoichiometric amounts of vimentin carrying the R113C point mutation disrupted the endogenous vimentin network in all tissues examined but caused a disease phenotype only in the eye lens, leading to a posterior cataract that was paralleled by the formation of extensive protein aggregates in lens fibre cells. Unexpectedly, central, postmitotic fibres became depleted of aggregates, indicating that they were actively removed. In line with an increase in misfolded proteins, the amounts of Hsp70 and ubiquitylated vimentin were increased, and proteasome activity was raised. We demonstrate here for the first time that the expression of mutated vimentin induces a protein-stress response that contributes to disease pathology in mice, and hypothesise that vimentin mutations cause cataracts in humans.
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PMID:A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice. 1894 Sep 12


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