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)

Aquaporin-0 (AQP0) is the major intrinsic protein of lens fiber cells and the founder member of the water channel gene family. Here we show that disruption of the AQP0 gene by an early transposon (ETn) element results in expression of a chimeric protein, comprised of approximately 75% AQP0 and approximately 25% ETn long terminal repeat (LTR) sequence, in the cataract Fraser (CatFr) mouse lens. Immunoblot analysis showed that mutant AQP0-LTR was similar in mass to wild-type AQP0. However, immunofluorescence microscopy revealed that AQP0-LTR was localized to intracellular membranes rather than to plasma membranes of lens fiber cells. Heterozygous CatFr lenses were similar in size to wild-type but displayed abnormal regions of translucence and light scattering. Scanning electron microscopy further revealed that mature fiber cells within the core of the heterozygous CatFr lens failed to stratify into uniform, concentric growth shells, suggesting that the AQP0 water channel facilitates the development of the unique cellular architecture of the crystalline lens.
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PMID:Disruption of lens fiber cell architecture in mice expressing a chimeric AQP0-LTR protein. 1105 41

Hfi is a dominant cataract mutation where heterozygotes show hydropic lens fibers and homozygotes show total lens opacity. The Hfi locus was mapped to the distal part of mouse chromosome 10 close to the major intrinsic protein (Mip), which is expressed only in cell membranes of lens fibers. Molecular analysis of Mip revealed a 76-bp deletion that resulted in exon 2 skipping in Mip mRNA. In Hfi/Hfi this deletion resulted in a complete absence of the wildtype Mip. In contrast, Hfi/+ animals had the same amount of wildtype Mip as +/+. Results from pulse-chase expression studies excluded hetero-oligomerization of wildtype and mutant Mip as a possible mechanism for cataract formation in the Hfi/+. We propose that the cataract phenotype in the Hfi heterozygote mutant is due to a detrimental gain of function by the mutant Mip resulting in either cytotoxicity or disruption in processing of other proteins important for the lens. Cataract formation in the Hfi/Hfi mouse is probably a combined result of both the complete loss of wildtype Mip and a gain of function of the mutant Mip.
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PMID:A 76-bp deletion in the Mip gene causes autosomal dominant cataract in Hfi mice. 1141 59

The possible role of ultraviolet light in the formation of cataract is not well understood. In this study, guinea pigs were exposed to a chronic, low level of UVA light (0.5 mWcm(-2), 340-410 nm wavelength, peak at 365 nm) for 4-5 months. It is known that the lens of the guinea pig possesses unusually high levels of the UVA chromophore NADPH. In a preliminary analysis, it was found that isolated guinea pig corneas transmitted 70-90% of 340-400 nm light, and that UVA radiation was able to penetrate deep into the nucleus of the guinea pig lens, where it was absorbed. Exposure of guinea pigs to UVA in vivo produced a 60% inactivation of lens epithelial catalase; however, analysis by transmission electron microscopy (TEM) showed no apparent morphological effects on either the lens epithelium or the cortex. A number of UVA-induced effects were found in the nucleus of the guinea pig lens, but were observed either not at all or to a lesser extent in the cortex. The effects included an increase in light scattering (two-fold; slit-lamp examination), distention of intercellular spaces (TEM), an increase in lipid peroxidation (30-35%; infrared spectroscopy), a decrease in GSH level (30%), an increase in protein-thiol mixed disulfide levels (80%), loss of water-soluble protein (20%), an increase in the amount of protein disulfide (two-fold; two-dimensional diagonal electrophoresis), degradation of MIP26 (15%) and loss of cytoskeletal proteins including actin, alpha- and beta- tubulin, vimentin and alpha-actinin (60-100%). The results indicate that a 4-5 month exposure of guinea pigs to a biologically relevant level of UVA light produces deleterious effects on the central region of the lenses of the animals. UVA radiation, coupled presumably with the photoreactive UVA chromophore NADPH and trace amounts of O(2) present in the lens nucleus, produced significant levels of oxidized products in the nuclear region over a five month period. The data demonstrate the potentially harmful nature of UVA light with respect to the lens, and highlight the importance of investigating a possible role for this type of radiation in the formation of human cataract.
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PMID:UVA light in vivo reaches the nucleus of the guinea pig lens and produces deleterious, oxidative effects. 1238 92

Cataract Tohoku (Cat(Tohm)) is a dominant cataract mutation that leads to severe degeneration of lens fiber cells. Linkage analysis showed that the Cat(Tohm) mutation is located on mouse chromosome 10, close to the gene for aquaporin-0 (Aqp0), which encodes a membrane protein that is expressed specifically in lens fiber cells. Sequence analysis of Aqp0 revealed a 12-bp deletion without any change in the reading frame, which resulted in a deletion of four amino acids within the second transmembrane region of the AQP0 protein. Targeted expression of the mutated Aqp0 caused lens opacity in transgenic mice, the pathological severity of which depended on the expression level of the transgene. The mutated AQP0 protein was localized to the intracellular and perinuclear spaces rather than to the plasma membranes of the lens fiber cells. The cataract phenotype of Cat(Tohm) is caused by a gain-of-function mutation in the mutated AQP0 protein and not by a loss-of-function mutation.
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PMID:Bilateral congenital cataracts result from a gain-of-function mutation in the gene for aquaporin-0 in mice. 1267 60

Corneas with edema-related diseases lose transparency, which causes significant vision loss. This study analyzed seven aquaporins (AQPs) in normal corneas, pseudophakic/aphakic bullous keratopathy (PBK/ABK) corneas, Fuchs' dystrophy corneas, keratoconus corneas, post-cataract surgery (PCS) corneas, and normal organ-cultured corneas. RNA levels for AQP1, AQP4, and beta2-microglobulin were measured by RT-PCR. AQP1 antibody localized to stromal cells of all corneas. PBK/ABK and Fuchs' dystrophy corneas had decreased endothelial cell staining compared with normal. AQP1 mRNA was found in whole corneas and cultured stromal fibroblasts but not in isolated epithelial cells. AQP3 staining was found in basal epithelial cells of the normal, Fuchs' dystrophy, and keratoconus corneas but throughout the entire epithelium of PBK/ABK corneas. AQP4 antibody localized to endothelial cells of all corneas and in stromal cells of PBK/ABK corneas. AQP4 mRNA was identified in whole human corneas. AQP5 was found in epithelial cells of all corneas. AQP0, AQP2, and AQP9 were not found in any corneas. Normal AQP distributions were found in PCS and organ-cultured corneas, although they showed signs of swelling. Our study demonstrates that AQP abnormalities are found in PBK/ABK corneas (decreased AQP1, increased AQP3 and AQP4) and Fuchs' dystrophy corneas (decreased AQP1). Although both have vision-disrupting corneal edema, the mechanisms of fluid accumulation may be different in each disease.
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PMID:Altered expression of aquaporins in bullous keratopathy and Fuchs' dystrophy corneas. 1538 80

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

Lens-specific Lp82 and ubiquitous m-calpain are neutral, calcium-activated, cysteine proteases. Both calpains are activated during rodent lens maturation and cataract formation. Lp85 calpain (Lens protein with MW=85 kDa) is a slightly larger splice variant of Lp82. Lp85 contains a 28 amino acid insert peptide (IS3) in calcium binding domain IV. Theoretically, the insert could alter the properties of Lp85 and influence proteolytic activity. The purpose of the present experiment was to compare the biochemical properties of Lp85 to Lp82 and m-calpain. Recombinant Lp85 and Lp82 were separately expressed using the baculovirus system and partially purified using Co2+ affinity and DEAE chromatographies. Calcium activation, pH dependency, and susceptibility to calpain inhibitors were assessed in a protease assay using BODIPY fluorescence-labeled casein substrate. Hydrolysis of lens proteins was assessed by SDS-PAGE and immunoblotting. Cleavage site analysis was performed by mass spectroscopy and Edman sequencing. Computer-based homology modeling was used to predict the influence of the IS3 region on the 3-dimensional structure of Lp85. Compared to m-calpain, Lp85 showed a lower calcium-activation requirement (K(50%act)=20 microM), marked insensitivity to, and cleavage of, the endogenous tissue inhibitor of calpains-calpastatin, and different preferred cleavage sites on alphaA-crystallin (five amino acid C-terminal truncation) and on aquaporin 0 (G239 and N246). Although the IS3 insert was predicted to form a loop protruding from the calcium binding region of Lp85, the biochemical properties of Lp85 studied were nearly identical to those of Lp82. Lp85 and Lp82 did not catalyze hydrolysis of each other, but both hydrolyzed m-calpain. Lp85 seems to be the enzymatic equivalent of Lp82. Both calpains could become active at lower cellular calcium levels than m-calpain. Lp85/Lp82 may have different functions than m-calpain since they cleave substrates at different sites. Lp85/Lp82 may regulate m-calpain activity by catalyzing the hydrolysis of calpastatin. The function of the IS3 insert on Lp85 remains unknown but is speculated to control subcellular distribution.
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PMID:Biochemical properties of lens-specific calpain Lp85. 1605 32

Aquaporin 0 (AQP0) is the major intrinsic protein of the lens and its water permeability can be modulated by changes in pH and Ca2+. The Cataract Fraser (Cat Fr) mouse accumulates an aberrant AQP0 (AQP0-LTR) in sub-cellular compartments resulting in a congenital cataract. We investigated the interference of AQP0-LTR with normal function of AQP0 in three systems. First, we created a transgenic mouse expressing AQP0 and AQP0-LTR in the lens. Expression of AQP0 did not prevent the congenital cataract but improved the size and transparency of the lens. Second, we measured water permeability of AQP0 co-expressed with AQP0-LTR in Xenopus oocytes. A low expression level of AQP0-LTR decreased the water permeability of AQP0, and a high expression level eliminated its calcium regulation. Third, we studied trafficking of AQP0 and AQP0-LTR in transfected lens epithelial cells. At low expression level, AQP0-LTR migrated with AQP0 toward the cell membrane, but at high expression level, it accumulated in sub-cellular compartments. The deleterious effect of AQP0-LTR on lens development may be explained by lowering water permeability and abolishing calcium regulation of AQP0. This study provides the first evidence that calcium regulation of AQP0 water permeability may be crucial for maintaining normal lens homeostasis and development.
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PMID:AQP0-LTR of the Cat Fr mouse alters water permeability and calcium regulation of wild type AQP0. 1651 71

The aquaporin (AQP) transmembrane proteins facilitate the movement of water across the plasma membrane. In the lens, AQP0 is expressed in fiber cells and AQP1 in the epithelium. Recently, two individuals were identified with congenital polymorphic autosomal dominant cataract, due to a single nucleotide base deletion mutation in the lens AQP0. The deletion modified the reading frame resulting in the addition of a premature stop codon. In the present study, we examined the water permeability properties, trafficking and dominant negative effects as well as cytotoxicity due to the mutant AQP0 (Delta213-AQP0) protein. The membrane water permeability (P(w)) of Delta213-AQP0 expressing oocytes (14+/-1 microm/s) was significantly lower than those expressing WT-AQP0 (25+/-3 microm/s). P(w) of water injected control oocytes was 13+/-2 microm/s. Co-expression of WT-AQP0 with Delta213-AQP0 significantly lowered the P(w) (18+/-3 microm/s) compared to WT-AQP0. With or without the EGFP tag, WT-AQP0 protein localized in the plasma membranes of oocytes and cultured cells whereas Delta213-AQP0 was retained in the ER. Forster Resonance Energy Transfer (FRET) showed that WT-AQP0 partly localized with the co-expressed Delta213-AQP0. Co-localization studies suggest that the mutant AQP0 gained its dominant function by trapping the WT-AQP0 in the ER through hetero-oligomerization. Incubating the cells with chemical chaperones, namely, TMAO and DMSO, did not correct the folding/trafficking defects. Cell death in the Delta213-AQP0 expressing cells was due to necrosis caused by the accumulation of Delta213-AQP0 protein in the ER in cytotoxic proportions. The data show that replacement of the distal end of the 6th TM domain and the C-terminal domain of AQP0 due to the deletion mutation resulted in the impairment of cell membrane P(w), localization of the mutant protein in the ER without trafficking to the plasma membrane, and cytotoxicity due to the accumulation of the mutant protein. Cataracts in patients with this mutation might have resulted from the above mentioned consequences.
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PMID:Functional characterization of a human aquaporin 0 mutation that leads to a congenital dominant lens cataract. 1850 47

In Xenopus oocytes, the water permeability of AQP0 (P(f)) increases with removal of external calcium, an effect that is mediated by cytoplasmic calmodulin (CaM) bound to the C terminus of AQP0. To investigate the effects of serine phosphorylation on CaM-mediated Ca(2+) regulation of P(f), we tested the effects of kinase activation, CaM inhibition, and a series of mutations in the C terminus CaM binding site. Calcium regulation of AQP0 P(f) manifests four distinct phenotypes: Group 1, with high P(f) upon removal of external Ca(2+) (wild-type, S229N, R233A, S235A, S235K, K238A, and R241E); Group 2, with high P(f) in elevated (5 mm) external Ca(2+) (S235D and R241A); Group 3, with high P(f) and no Ca(2+) regulation (S229D, S231N, S231D, S235N, and S235N/I236S); and Group 4, with low P(f) and no Ca(2+) regulation (protein kinase A and protein kinase C activators, S229D/S235D and S235N/I236S). Within each group, we tested whether CaM binding mediates the phenotype, as shown previously for wild-type AQP0. In the presence of calmidazolium, a CaM inhibitor, S235D showed high P(f) and no Ca(2+) regulation, suggesting that S235D still binds CaM. Contrarily, S229D showed a decrease in recruitment of CaM, suggesting that S229D is unable to bind CaM. Taken together, our results suggest a model in which CaM acts as an inhibitor of AQP0 P(f). CaM binding is associated with a low P(f) state, and a lack of CaM binding is associated with a high P(f) state. Pathological conditions of inappropriate phosphorylation or calcium/CaM regulation could induce P(f) changes contributing to the development of a cataract.
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PMID:Phosphorylation determines the calmodulin-mediated Ca2+ response and water permeability of AQP0. 1850 73


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