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)

Mutations of connexin alpha 8 (GJA8 or Cx50) and connexin alpha 3 (GJA3 or Cx46) in humans have been reported to cause cataracts with semi-dominant inheritance patterns. Targeted null mutations in Gja8 and Gja3 in mice cause cataracts with recessive inheritance. The molecular bases for these differences in inheritance patterns and the mechanism for cataractogenesis in these mutants are poorly understood. We recently mapped an autosomal semi-dominant cataract [lens opacity 10 (Lop10)] mutation to mouse chromosome 3 and identified a missense mutation (G-->C) in the Gja8 gene, which causes glycine at codon 22 to be replaced with arginine (G22R). Moreover, we demonstrated that the alpha 8 G22R isoform is a loss-of-function mutant for alpha 8, as well as a dominant mutation for reducing the phosphorylated forms of alpha 3 connexin in vivo. To test the hypothesis that the alteration of endogenous alpha 3 connexin in Lop10 mice led to a unique lens phenotype, we generated double mutant offspring between Lop10 and the Gja3(tm1) (alpha 3(-/-)) mice. The double homozygous mutant mice (Lop10/Lop10 alpha 3(-/-)) showed relatively normal lens cortical fibers compared to the Lop10 mice. A functional impairment of endogenous alpha 3 connexin is therefore partly responsible for cellular phenotypes in the Lop10 mice. This study has provided some novel molecular insights into mouse and human cataractogenesis caused by alpha 8 and alpha 3 mutations. These mouse models will be useful for investigating the mechanistic relationship between gap junction impairment and cataract formation.
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PMID:A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice. 1187 45

Chemical gating of gap junction channels by intracellular pH may be an important mechanism for the physiological regulation of cell-cell coupling. In the ocular lens, pH gating of gap junction channels has been implicated as a possible cause of cataract in diabetics. To address this question further, I determined the pH dependence of the rat connexin (Cx)-46 and ovine Cx49 in transfected HeLa cells using the pH-clamp technique during dual whole-cell recording. pH gating for both connexins was fast and reversible. The apparent p K(a) (p K(a,app)) was 6.66 +/- 0.01 and the Hill coefficient ( n) 6.8 +/- 1.8 for Cx49, and for Cx46 6.8 +/- 0.01 and 2.2 +/- 0.15, respectively. C-terminal truncation of Cx46 by 163 aa did not abolish the pH sensitivity but shifted the p K(a,app) to 6.6 +/- 0.01. This finding is inconsistent with the ball-and-chain model proposed for Cx43. Voltage gating of Cx46 channels was also not altered by truncation or acidic pH, indicating that the two gating mechanisms are functionally and possibly structurally separate. The data also imply a significant role of pH gating for lens pathophysiology. For the normal pH range in the lens cortex (pH 6.8-7.2) most gap junction channels will be open. However, mild acidification will reduce gap junctional coupling significantly, especially for Cx50 channels. Localized closure of gap junction channels will disrupt lens transport and thus may contribute to the tissue damage observed in diabetic lenses.
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PMID:pH gating of lens fibre connexins. 1188 84

Gap junctional intercellular communication plays an important role in the maintenance of cellular homeostasis. The flow of chemical messengers through gap junctions, gap junctional intercellular communication, is essential in processes such as electrical coupling, embryonic development and adaptive tissue response. Gap junctions are formed by connexin proteins. Mutational alterations in the connexin genes are associated with the occurrence of multiple diseases, such as peripheral neuropathy, cardiovascular disease, dermatological disease, hereditary deafness and cataract. Consequently, modulation of gap junctional intercellular communication is a potential pharmacological target. Future research, based, for example, on the recent developments in genetics, may clarify gap junction physiology. This will in turn provide promising perspectives for the development of targeted drugs.
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PMID:[The role of intercellular communication via "gap junctions" in disease]. 1470 10

To investigate the effects of Rho GTPase inactivation on lens fiber cell cytoskeletal and morphological integrity, a transgenic mouse model expressing C3-exoenzyme (a bacterial toxin) in a lens-specific manner was utilized. Cryosections of whole eyes from C3 transgenic mice and littermate controls were stained for F-actin with rhodamine-phalloidin or immunostained for beta-catenin, aquaporin-0 or connexin-50, and confocal images were recorded. Lens fiber cell morphology was examined at both light and electron microscopic levels. To investigate the influence of Rho GTPase inactivation on the profiles of gene expression, cDNA libraries generated from transgenic and littermate control mouse lenses were screened by cDNA microarray analysis. In contrast to the wild-type lens, fiber cells of the transgenic lens were grossly swollen and disorganized, with abnormal membrane architecture. Staining of F-actin, beta-catenin, aquaporin-0 and connexin-50 was reduced dramatically in the C3 transgenic lens as compared to controls. Western blot analysis and cDNA microarray analysis did not reveal any noticeable decreases in actin, beta-catenin and aquaporin-0 protein levels or expression in C3 transgenic lenses, indicating that altered cytoskeletal organization in response to Rho GTPase inactivation might underlie the noted changes in staining for these proteins. Additionally, cDNA microarray analysis of C3 lens revealed altered expression (at least two-fold, compared to littermate controls) of 44 genes. These include genes encoding extracellular matrix and basement membrane proteins, cell survival and apoptotic pathways, and ion and protein transport. These data indicate that disruption of Rho GTPase function in the developing mouse lens results in abnormal cytoskeletal organization, fiber cell interactions, impaired lens fiber cell morphology and altered gene expression of cellular proteins involved in diverse functions. This work reveals that the morphological and cytoskeletal abnormalities triggered upon Rho GTPase inactivation in lens could be one of the important insults associated with cataract formation in C3 transgenic mouse lens.
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PMID:Impaired cytoskeletal organization and membrane integrity in lens fibers of a Rho GTPase functional knockout transgenic mouse. 1509 15

There is a good deal of evidence that the lens generates an internal micro circulatory system, which brings metabolites, like glucose, and antioxidants, like ascorbate, into the lens along the extracellular spaces between cells. Calcium also ought to be carried into the lens by this system. If so, the only path for Ca2+ to get out of the lens is to move down its electrochemical gradient into fiber cells, and then move by electrodiffusion from cell to cell through gap junctions to surface cells, where Ca-ATPase activity and Na/Ca exchange can transport it back into the aqueous or vitreous humors. The purpose of the present study was to test this calcium circulation hypothesis by studying calcium homeostasis in connexin (Cx46) knockout and (Cx46 for Cx50) knockin mouse lenses, which have different degrees of gap junction coupling. To measure intracellular calcium, FURA2 was injected into fiber cells, and the gradient in calcium concentration from center to surface was mapped in each type of lens. In wild-type lenses the coupling conductance of the mature fibers was approximately 0.5 S/cm2 of cell to cell contact, and the best fit to the calcium concentration data varied from 700 nM in the center to 300 nM at the surface. In the knockin lenses, the coupling conductance was approximately 1.0 S/cm2 and calcium varied from approximately 500 nM at the center to 300 nM at the surface. Thus, when the coupling conductance doubled, the concentration gradient halved, as predicted by the model. In knockout lenses, the coupling conductance was zero, hence the efflux path was knocked out and calcium accumulated to approximately 2 microM in central fibers. Knockout lenses also had a dense central cataract that extended from the center to about half the radius. Others have previously shown that this cataract involves activation of a calcium-dependent protease, Lp82. We can now expand on this finding to provide a hypothesis on each step that leads to cataract formation: knockout of Cx46 causes loss of coupling of mature fiber cells; the efflux path for calcium is therefore blocked; calcium accumulates in the central cells; at concentrations above approximately 1 microM (from the center to about half way out of a 3-wk-old lens) Lp82 is activated; Lp82 cleaves cytoplasmic proteins (crystallins) in central cells; and the cleaved proteins aggregate and scatter light.
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PMID:Connections between connexins, calcium, and cataracts in the lens. 1545 95

Gap junctions are clusters of intercellular channels that provide morphological support for direct diffusion of ions and low-molecular-weight molecules between adjacent coupled cells. Each gap junction channel is made by docking of two hemichannels or connexons, each formed by assembly of six proteins (connexins). 21 members of the connexin gene family are likely to be expressed in the human genome. These ubiquitous gated channels, allowing rapid intercellular communication and synchronisation of coupled cell activities, play critical roles in many signalling processes, including co-ordinated cardiac and smooth muscle contractions, neuronal excitability, neurotransmitter release, insulin secretion, epithelial electrolyte transport, etc. Mutational alterations in the connexin genes are associated with the occurrence of multiple pathologies, such as peripheral neuropathies, cardiovascular diseases, dermatological diseases, hereditary deafness and cataract. But the neuro- and cardioprotective effects of blocking agents of junctional channels show that closure of these channels may also be beneficial in certain pathological situations. Consequently, modulation of gap junctional intercellular communication is a potential pharmacological target. In contrast to most other membrane channels, no natural toxin or specific inhibitor of junctional channels has been identified yet and most uncoupling agents generally also affect other ionic channels and receptors. Future research, based for example on the recent developments in genetics, may clarify gap junction physiology. This will in turn provide promising perspectives for the development of targeted drugs.
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PMID:Connexin-made channels as pharmacological targets. 1597 69

Connexins, that have their main function as part of gap junction channels, are proteins expressed in a large number of tissues such as endocrine, nervous, vascular, and muscular tissues. Gap junctions are implicated in tissue homeostasis and control of cell proliferation and differentiation. Interestingly, mutations of connexin genes have been reported in several human diseases (peripheral neuropathies, cardiovascular and dermatological diseases, hereditary cataract, and deafness) and altered expression of connexins have been associated with tumoral progression. Today, several lines of study argue for a critical role of gap junctions in corporal smooth muscle relaxation and erectile response. The present review highlights the emerging role of connexin43, one of these membranous proteins, in the physiology and physiopathology of human erectile function and its possible medical application.
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PMID:Connexin43: emerging role in erectile function. 1667 45

A G22R point mutation in alpha8 connexin (Cx50) has been previously shown to cause a severe cataract by interacting with endogenous wild-type alpha3 connexin (Cx46) in mouse lenses. Here, we tested whether a knocked-in alpha3 connexin expressed on the locus of the endogenous alpha8 connexin could modulate the severe cataract caused by the alpha8-G22R mutation. We found that the alpha3(-/-) alpha8(G22R/-) mice developed severe cataracts with disrupted inner fibers and posterior rupture while the alpha3(-/-) alpha8(G22R/KIalpha3) lens contained relatively normal inner fibers without lens posterior rupture. The alpha8-G22R mutant proteins produced typical punctate staining of gap junctions between fiber cells of alpha3(-/-) alpha8(G22R/KIalpha3) lenses, but not in those of alpha3(-/-) alpha8(G22R/-) lenses. Thus, we hypothesize that the knocked-in alpha3 connexin subunits interact with the alpha8-G22R connexin subunits to form functional gap junction channels and rescue the lens phenotype. Using an electrical coupling assay consisting of paired Xenopus oocytes, we demonstrated that only co-expression of mutant alpha8-G22R and wild-type alpha3 connexin subunits forms functional gap junction channels with reduced conductance and altered voltage sensitivity compared with the channels formed by alpha3 connexin subunits alone. Thus, knocked-in alpha3 connexin and mutant alpha8-G22R connexin probably form heteromeric gap junction channels that influence lens homeostasis and lens transparency.
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PMID:Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation. 1668 38

Lens development and transparency have been hypothesized to depend on intercellular gap junction channels, consisting of alpha3 (Cx46) and alpha8 (Cx50) connexin subunits, to transport metabolites, secondary messages and ions between lens cells. To evaluate this hypothesis, we have generated alpha3(-/-) alpha8(-/-) double knockout mice and characterized their lens phenotypes. Without gap junctions between lens fiber cells, alpha3(-/-) alpha8(-/-) lenses displayed severe cataracts resulting from cell swelling and degeneration of inner fibers while normal peripheral fiber cells continued to form throughout life. Neither an increase of degraded crystallins nor an increase of water-insoluble crystallins was found in alpha3(-/-) alpha8(-/-) lenses. However, a substantial reduction of gamma-crystallin proteins, but not alpha- and beta-crystallins, was detected. These results suggest that gap junction communication is important for maintaining lens homeostasis of inner fiber cells and that a loss of gap junctions leads to cataract formation as well as reductions of gamma-crystallin proteins and transcripts.
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PMID:Absence of alpha3 (Cx46) and alpha8 (Cx50) connexins leads to cataracts by affecting lens inner fiber cells. 1669 70

Worldwide, ocular cataracts are a major cause of human blindness. A key goal of cataract-related research is to identify simple, cost-efficient but effective ways to prevent cataract formation or progression. Genistein is a naturally occurring dietary isoflavone with well-documented estrogenic, antioxidant, and protein tyrosine kinase inhibitor activity, which in turn modulates the activity of several enzymes involved in cell signaling and proliferation. Furthermore, many isoflavones have been shown to be potent inhibitors of aldose reductase, which is an important rate-limiting enzyme in the process of cataract induction in the metabolic disease galactosemia. In order to assess the potential for genistein to mitigate cataract formation, we have studied its effects in the animal model of dietary galactose-induced cataracts in adult male rats. Our experimental hypothesis was that dietary genistein would prevent or delay the progression of cataracts induced by high dietary intake of galactose. Our results show that the isoflavone genistein was not able to completely prevent galactose-induced cataract formation, but genistein did delay the progression of cataracts induced by dietary galactose. In addition, we found that dietary galactose decreased concentrations of serum somatostatin, while adding genistein decreased the serum glucose level but increased the serum testosterone level. As an initial inquiry into the mechanisms by which the partial protective effect of genistein could be mediated, we found that genistein increased the expression of connexin (Cx) 43 in the lens but did not affect the expression of soluble guanylyl cyclase (sGC) subunits. This finding suggests that the partial protective effect of genistein on cataract induction appears to be unrelated to sGC but may be mediated by enhanced expression of Cx43 and changed metabolic state.
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PMID:Effect of the isoflavone genistein against galactose-induced cataracts in rats. 1720 92


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