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 present study was undertaken to analyse the relationship of lens glutathione (GSH) and light to cataract development in mice deficient in gamma-glutamyl transpeptidase (GGT). These mice have reduced levels of cysteine and GSH in the eye and develop cataracts. GGT-deficient mice raised under normal vivarium conditions, showed no cataractous changes at birth, but by 1 week they had developed nuclear opacities. By 3 weeks more severe cataracts develop, and lens GSH levels are approximately 6-7% of wild type levels. By 6-11 weeks cataracts show nuclear and cortical involvement, liquefaction and calcification. Single cell DNA electrophoresis (comet assay) demonstrated mild DNA damage in the lens epithelium. GGT-deficient mice raised in the dark beginning the day after conception all developed cataracts, but these were less severe than those in GGT-deficient mice raised with normal vivarium lighting. Administration of N -acetyl cysteine (NAC) raises lens GSH and almost completely prevents cataract development. Our data indicate that cataract development in GGT-deficient mice is multifactorial and results from exogenous damage (exposure to light), reduced lens GSH levels, and nutritional effects secondary to low cysteine levels.
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PMID:Cataract development in gamma-glutamyl transpeptidase-deficient mice. 1109 9

The aim of the study is to screen patients for homocystinuria with and without cataract and analyse for homocystine and methionine. Fifty-eight samples from 29 patients, i.e., plasma and urine collected after overnight fasting were analysed by the screening test for homocystine, and paper chromatography for homocystine and methionine. Out of 29 homocystinuric patients, 24 had cataract. Only one had appreciable amounts of methionine in his serum. He also had mental retardation as expected and belongs to Type I. The other types did not have methionine but had only homocystine. There was no mental retardation or ectopia lentis. So they belonged to Types II, III or IV. As there is excess methionine in Type I, with low cystine, cataract may be due to deficiency of cysteine and reduced glutathione and might be averted by suitable therapy, i.e., high cystine-low methionine diet with B6. In other types with low methionine, cataract may be due to decreased availability of amino acids for the synthesis of lens proteins; the treatment of choice should be B12, and folate with methionine.
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PMID:Homocystinuria with congenital/developmental cataract. 1110 22

Disulfide cross-linking, one of the results of oxidative stress, has been thought to play an important role in cataractogenesis. High molecular mass (HMM) protein aggregation also contributes to cataract development, and a prevailing speculation is that disulfide cross-linking induces HMM aggregation. However, there is no direct evidence to support this speculation. Dimerization is an effect of disulfide cross-linking but cannot explain the size of HMM aggregates observed in the lens. alphaA-crystallin has two cysteine residues (Cys131 and Cys142) and we have prepared three Cys-deficient mutants, two single mutants (C131I and C142I) and one double mutant (C131I/C142I). They were subjected to H202 oxidation in an ascorbate-FeCl(3)-EDTA-H202 system. The effects of oxidation on the mutants, including changes in aggregate size and conformation, were compared with those of the wild-type alphaA-crystallin by FPLC gel filtration, absorption, fluorescence, and circular dichroism measurements. The results indicated that other amino acid residues besides Cys, such as Trp and Tyr, were also oxidized by H202. Disulfide dimerization alone seems to play a less important role in HMM aggregation than does the secondary conformational change resulting from the combined effect of the oxidation of Trp and Tyr as well as Cys.
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PMID:Oxidation of human lens recombinant alphaA-crystallin and cysteine-deficient mutants. 1116 7

The calpains form a growing family of structurally related intracellular multidomainal cysteine proteinases, which exhibit a catalytic domain distantly related to papain. In contrast to papain, however, their activity in most cases depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but have also been implicated in muscular dystrophy, ischemia, traumatic brain injury, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains are the ubiquitously expressed mu- and m-calpains, consisting of a common 30 kDa small S-subunit (domains V and VI) and slightly differing 80 kDa large L-subunits (domains I to IV). We have recently determined the 2.3 A structure of recombinant full-length human m-calpain in the absence of calcium, which reveals that the catalytic domain and the two calmodulin-like domains, previously believed to represent the unique calcium switch, are not positioned adjacent to each other, but are separated by the beta-sandwich domain III, which distantly resembles C2 domains. Although the catalytic domain of apocalpain is strongly disrupted compared to papain (which explains its inactivity in the absence of calcium), the crystal structure reveals several sites where calcium could bind, thereby causing a subdomain fusion to form a papain-like catalytic center. All current evidence points to the cooperative interaction of several calcium binding sites. Sites identified include the three EF-hand binding sites in each calmodulin-like domain, the negatively charged segments arranged around the active-site cleft (provided by both catalytic subdomains), as well as an exposed acidic loop of domain III, whose charge compensation could allow the adjacent barrel-like subdomain IIb to move toward the helical subdomain IIa. The Gly-rich S-chain N-terminus and the calcium-loaded acidic loop could target the conventional calpains to cellular/nuclear membranes, thereby explaining their strongly reduced calcium requirement in vivo and in vitro in the presence of acidic phospholipids.
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PMID:Structural basis for possible calcium-induced activation mechanisms of calpains. 1151 28

Mitochondrial cytochrome b mutations have been reported to have a homogenous phenotype of pure exercise intolerance. We describe a novel mutation in the cytochrome b gene of mitochondrial DNA (A15579G) associated with a selective decrease of muscle complex III activity in a patient who, besides severe exercise intolerance, also has multisystem manifestations (deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, epilepsy). The point mutation is heteroplasmic in muscle (88%) and leukocytes (15%), and changes a highly conserved tyrosine to cysteine at amino acid position 278.
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PMID:Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. 1160 7

The calpains form a growing family of structurally related intracellular multidomain cysteine proteinases containing a papain-related catalytic domain, whose activity depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but are also implicated in muscular dystrophy, cardiac and cerebral ischemia, platelet aggregation, restenosis, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains, the ubiquitously expressed mu- and m-calpains, are heterodimers consisting of a common 30-kDa small and a variable 80-kDa subunit. The recently determined crystal structures of human and rat m-calpain crystallized in the absence of calcium essentially explain the inactivity of the apoform by catalytic domain disruption, indicate several sites where calcium could bind causing reformation of a papain-like catalytic domain, and additionally reveal modes by which phospholipid membranes could reduce the calcium requirement. Current evidence points to a cooperative interaction of several sites, which, upon calcium binding, trigger the reformation of a papain-similar catalytic domain.
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PMID:The structure of calcium-free human m-calpain: implications for calcium activation and function. 1167 52

The cysteine residues of the gamma crystallins, a family of ocular lens proteins, are involved in the aggregation and phase separation of these proteins. Both these phenomena are implicated in cataract formation. We have used bovine gammaB crystallin as a model system to study the role of the individual cysteine residues in the aggregation and phase separation of the gamma crystallins. Here, we compare the thermodynamic and kinetic behavior of the recombinant wild-type protein (WT) and the Cys18 to Ser (C18S) mutant. We find that the solubilities of the two proteins are similar. The kinetics of crystallization, however, are different. The WT crystallizes slowly enough for the metastable liquid-liquid coexistence to be easily observed. C18S, on the other hand, crystallizes rapidly; the metastable coexisting liquid phases of the pure mutant do not form. Nevertheless, the coexistence curve of C18S can be determined provided that crystallization is kinetically suppressed. In this way we found that the coexistence curve coincides with that of the WT. Despite the difference in the kinetics of crystallization, the two proteins were found to have the same crystal forms and almost identical X-ray structures. Our results demonstrate that even conservative point mutations can bring about dramatic changes in the kinetics of crystallization. The implications of our findings for cataract formation and protein crystallization are discussed.
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PMID:Enhanced crystallization of the Cys18 to Ser mutant of bovine gammaB crystallin. 1173 87

alphaA-crystallin is a small heat-shock protein expressed preferentially in the lens and is detected during the early stages of lens development. Recent work indicates that the expression of alphaA-crystallin enhances lens epithelial cell growth and resistance to stress conditions. Mutation of the arginine 116 residue to cysteine (R116C) in alphaA-crystallin has been associated with congenital cataracts in humans. However, the physiological consequences of this mutation have not been analyzed in lens epithelial cells. In the present study, we expressed wild type or R116C alphaA-crystallin in the human lens epithelial cell line HLE B-3. Immunofluorescence and confocal microscopy indicated that both wild type and R116C alphaA-crystallin were distributed mainly in the cytoplasm of lens epithelial cells. Size-exclusion chromatography indicated that the size of the alphaA-crystallin aggregate in lens epithelial cells increased from 500 to 600 kDa for the wild type protein to >2 MDa in the R116C mutant. When cells were exposed to physiological levels of UVA radiation, wild type alphaA-crystallin protected cells from apoptotic death as shown by annexin labeling and flow cytometric analysis, whereas the R116C mutant had a 4- to 10-fold lower protective ability. UVA-irradiated cells expressing the wild type protein had very low TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining, whereas cells expressing R116C mutant had a high level of TUNEL staining. F-actin was protected in UVA-treated cells expressing the wild type alphaA-crystallin but was either clumped around the apoptotic cells or was absent in apoptotic cells in cultures expressing the R116C mutant. Structural changes caused by the R116C mutation could be responsible for the reduced ability of the mutant to protect cells from stress. Our study shows that comparing the stress-induced apoptotic cell death is an effective way to compare the protective abilities of wild type and mutant alphaA-crystallin. We propose that the diminished protective ability of the R116C mutant in lens epithelial cells may contribute to the pathogenesis of cataract.
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PMID:The R116C mutation in alpha A-crystallin diminishes its protective ability against stress-induced lens epithelial cell apoptosis. 1175 14

Recent results indicate that covalent modification of proteins by tryptophan-derived UV filters may explain the age-dependent coloration of human lenses, and play a role in age-related cataract. The sites of attachment of the UV filters to the lens crystallins, however, have not been determined. This study utilized a database of predicted masses of UV filter-modified tryptic peptides to target sites of UV filter attachment. Proteins were isolated from old normal lenses and digested with trypsin at pH 6, in order to preserve the integrity of the sites of modification. Peptides were separated by high-performance liquid chromatography and characterized by mass spectrometry. Major colored and fluorescent peaks in the digest were found to correspond to cysteine-containing peptides in which the sulfur atom of the sidechain was linked to the major UV filter compound, 3-hydroxykynurenine glucoside. Three of the peptides originated from gammaS-crystallin and one from betaB1-crystallin. These results show that a predicted mass database can be used to facilitate the identification of sites of UV filter modification in human lens crystallins. Furthermore, this work represents the first evidence that UV filters bind to specific residues on lens proteins in vivo, and suggests that sulfhydryl groups may be important sites for the attachment of UV filters.
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PMID:Identifying sites of attachment of UV filters to proteins in older human lenses. 1198 16

The lens capsule, which is also called the lens basement membrane, is a specialized extracellular matrix produced anteriorly by the lens epithelium and posteriorly by newly differentiated fiber cells. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein that regulates cell-cell and cell-matrix interactions, cellular proliferation and differentiation, and the expression of genes encoding extracellular matrix components. SPARC-null mice exhibit lens opacity 1 month after birth and mature cataract and capsular rupture at 5-7 months. In this study, we report disruption of the structural integrity of the lens capsule in mice lacking SPARC. The major structural protein of basement membrane, collagen type IV, in the lens capsule was substantially altered in the absence of SPARC. The lens cells immediately beneath the capsule showed aberrant morphology, with numerous protrusions into the lens basement membrane. SPARC-null lenses at 1 month of age exhibited an increased penetration of dye or radioactive tracer through the capsule, as well as a higher content of water than their wild-type counterparts. Moreover, SPARC-null fibers exhibited swelling as early as 1 month of age; by 3 months, all the fiber cells appeared swollen to a marked degree. By contrast, the absence of SPARC had no apparent morphological effect on the early stages of lens formation, cell proliferation or fiber cell differentiation. Degradation of crystallins and MIP 26, or changes in the levels of these proteins, were not detected. These results underscore the importance of the capsular extracellular matrix in the maintenance of lens transparency and indicate that SPARC participates in the synthesis, assembly and/or stabilization of the lens basement membrane.
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PMID:Alterations in the lens capsule contribute to cataractogenesis in SPARC-null mice. 1207 65


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