Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For cell replacement therapies of retinal diseases, the most-needed cells are retinal pigment epithelial cells and photoreceptor cells; lens cells are needed for replacement of the cataract. Stromal cell-derived inducing activity induces the differentiation of mouse embryonic stem (ES) cells into neural cells, including midbrain tyrosine hydroxylase-positive dopaminergic neurons, and ocular cells; the method also works with primate ES cells. We describe the methods to induce retinal pigment epithelial and lens cells from monkey ES cells using stromal cell-derived inducing activity and show the characteristics of those cells in vitro and in vivo.
Methods Mol Biol 2006
PMID:Derivation and characterization of lentoid bodies and retinal pigment epithelial cells from monkey embryonic stem cells in vitro. 1684 40

An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and micrencephaly, with associated functional and behavioral problems. Defects of craniofacial development including clefts, the axial and appendicular skeleton, the body wall, teeth, and heart are also commonly found. Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Suggested future human studies include problems of CNS function after exposure to influenza and fever, including mental retardation, schizophrenia, autism, and cerebral palsy.
Birth Defects Res A Clin Mol Teratol 2006 Jul
PMID:Review: Hyperthermia and fever during pregnancy. 1693 4

Hereditary childhood cataracts can arise from single-point mutations in genes encoding crystallins, the major protein components of the lens. The cataracts are most commonly inherited by an autosomal dominant mechanism. The nature of the changes in the lens resulting from these point mutations in crystallin genes has not been fully characterised. While aggregation and light scattering associated with expression of the mutant crystallin protein may be an end point, it is also necessary to determine the progression of changes induced at the level of development and differentiation. A key finding in recent work is that cell death or cytotoxicity is associated with mutations in alpha A-crystallin. The variable morphology or localisation of the cataract in different pedigrees, even with the identical crystallin gene mutation, has led to the idea that other environmental or genetic factors interact to give the final lens phenotype. The study of mechanisms of formation of hereditary cataracts may lead to a greater understanding of the mechanisms that lead to age-related cataracts, a very common cause of blindness in the ageing population.
Expert Rev Mol Med 2006 Oct 19
PMID:Crystallins and hereditary cataracts: molecular mechanisms and potential for therapy. 1704 4

Although cataract is a characteristic feature of myotonic dystrophy type 1 (DM1), little is known of the underlying mechanisms. We generated four lens epithelial cell lines derived from DM1 cataracts and two from age-matched, non-DM cataracts. Small-pool PCR revealed typical large triplet repeat expansions in the DM1 cells. Furthermore, real-time PCR analysis showed reduced SIX5 expression and increased expression of the Ca(2+)-activated K(+) channel SK3 in the DM1 cells. These cells also exhibited longer population doubling times which did not arise through reduced proliferation, but rather increased cell death as shown by increased release of lactate dehydrogenase (LDH). Using (86)Rb(+) as a tracer for K(+), we found no difference in the resting K(+) influx or efflux kinetics. In all cases, the ouabain sensitive component of the influx contributed approximately 50% of the total. However, stimulating internal Ca(2+) by exposure to ionomycin not only caused greater stimulation of K(+) ((86)Rb) efflux in the DM1 cells but also induced a higher rate of cell death (LDH assay). Since both the hyper-stimulation of K(+) efflux and cell death were reduced by the highly specific SK inhibitor apamin, we suggest that increased expression of SK3 has a critical role in the increased Ca(2+)-induced fragility in DM1 cells. The present data, therefore, both help explain the lower epithelial cell density previously observed in DM1 cataracts and provide general insights into mechanisms underlying the fragility of other DM1-affected tissues.
Hum Mol Genet 2006 Dec 15
PMID:Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility. 1710 31

Transforming growth factor-beta2 (TGF-beta2) is one of the most important immunosuppressive cytokines in the anterior chamber of the eye. It is secreted as a complex with latency-associated peptide as an inactive precursor. Only the activated form of TGF-beta2 can bind to its receptor and induce signaling. To date, the concentration of active TGF-beta2 in aqueous humor was exclusively determined using samples that had been preserved at -80 degrees C. Quantitative measurements of the activated form directly after sampling have not yet been taken. The aim of this study was to investigate the effect of cryopreservation on the concentration of active TGF-beta2 in the aqueous humor. Samples of aqueous humor were drawn from patients with either cataract or a corneal disorder for determination of TGF-beta2 using a Sandwich-ELISA. In group I (n=30, patients with corneal disorders or cataract), one part of each sample was tested for active TGF-beta2 directly after sampling, whereas the remaining material was stored at -80 degrees C for later analysis. Group II consisted of patients undergoing a simple cataract extraction (n=38), and active TGF-beta2 levels were determined within 3 h after sampling. In Group III (n=34, patients with corneal disorders or cataract), active TGF-beta2 was determined within 3 h after puncture, as were total TGF-beta2 levels after acidic activation for each sample. The average level of active TGF-beta2 in the aqueous humor of group I analyzed directly after sampling was 35+/-31 (median 37) pg/ml. In contrast, frozen samples from the same patients showed an average concentration of 155+/-103 (median 152) pg/ml. The average level of active TGF-beta2 in aqueous humor of 38 cataract (group II) eyes was 40+/-24 (median 41) pg/ml determined within 3 h after puncture. The average level of total TGF-beta2 in group III was 1,654+/-631 (median 1,542) pg/ml compared to 33+/-39 (median 28) pg/ml of active TGF-beta2 determined directly after sampling, yielding a ratio of 2% of active to total TGF-beta2. Levels of active TGF-beta2 in aqueous humor determined directly after sampling were 4.4 fold lower than those measured in frozen samples. Thus, samples meant for determining active TGF-beta2 levels should not be kept frozen.
Mol Vis 2006 Dec 02
PMID:Determination of active TGF-beta2 in aqueous humor prior to and following cryopreservation. 1716 3

MAF, one of a family of large Maf bZIP transcription factors, is mutated in human developmental ocular disorders that include congenital cataract, microcornea, coloboma and anterior segment dysgenesis. Expressed early in the developing lens vesicle, it is central to regulation of lens crystallin gene expression. We report a semi-dominant mouse c-Maf mutation recovered after ENU mutatgenesis which results in the substitution, D90V, at a highly conserved residue within the N-terminal 35 amino-acid minimal transactivation domain (MTD). Unlike null and loss-of-function c-Maf mutations, which cause severe runting and renal abnormalities, the phenotype caused by the D90V mutation is isolated cataract. In reporter assays, D90V results in increased promoter activation, a situation similar to MTD mutations of NRL that also cause human disease. In contrast to wild-type protein, the c-Maf D90V mutant protein is not inhibited by protein kinase A-dependent pathways. The MTD of large Maf proteins has been shown to interact with the transcriptional co-activator p300 and we demonstrate that c-Maf D90V enhances p300 recruitment in a cell-type dependent manner. We observed the same for the pathogenic human NRL MTD mutation S50T, which suggests a common mechanism of action.
Hum Mol Genet 2007 May 01
PMID:A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation. 1737 26

The eye lens is packed with soluble crystallin proteins, providing a lifetime of transparency and light refraction. gamma-Crystallins are major components of the dense, high refractive index central regions of the lens and generally have high solubility, high stability and high levels of cysteine residues. Human gammaC belongs to a group of gamma-crystallins with a pair of cysteine residues at positions 78 and 79. Unlike other gamma-crystallins it has relatively low solubility, whereas mouse gammaC, which has the exposed C79 replaced with arginine, and a novel mouse splice variant, gammaCins, are both highly soluble. Furthermore, human gammaC is extremely stable, while the mouse orthologs are less stable. Evolutionary pressure may have favoured stability over solubility for human gammaC and the reverse for the orthologs in the mouse. Mutation of C79 to R79, in human gammaC, greatly increased solubility, however, neither form produced crystals. Remarkably, when the human gammaD R36S crystallization cataract mutation was mimicked in human gammaC-crystallin, the solubility of gammaC was dramatically increased, although it still did not crystallize. The highly soluble mouse gammaC-crystallin did crystallize. Its X-ray structure was solved and used in homology modelling of human gammaC, and its mutants C79R and R36S. The human gammaD R36S mutant was also modelled from human gammaD coordinates. Molecular dynamics simulation of the six molecules in the solution state showed that the human gammaCs differed from gammaDs in domain pairing, behaviour that correlates with interface sequence changes. When the fluctuations of the calculated molecular dipoles, for the six structures, over time were analysed, characteristic patterns for soluble gammaC and gammaD proteins were observed. Individual sequence changes that increase or decrease solubility correlated well with changes in the magnitude and direction of these dipoles. It is suggested that changes in surface residues have allowed adaptation for the differing needs of human and mouse lenses.
J Mol Biol 2007 Sep 07
PMID:Biophysical properties of gammaC-crystallin in human and mouse eye lens: the role of molecular dipoles. 1765 3

Mutation of the glycine 98 residue to arginine in alphaA-crystallin has been shown to cause presenile cataract in an Indian family. Our earlier study showed that the mutant protein exhibits folding defects that lead to aggregation and inclusion body formation in Escherichia coli. Despite the presence of a normal copy, the pathology is seen in the heterozygous individuals. Formation of mixed oligomers between wild-type and the mutant subunits might be crucial for manifestation of such dominant negative character. We have investigated the role of G98R mutation in alphaA-crystallin in its structural stability and subunit exchange. G98R alphaA-crystallin unfolds at lower concentrations of urea compared to wild-type alphaA-crystallin. The mutant protein is more susceptible to proteolysis than the wild-type protein and transiently populates fragments that are prone to aggregation. Subunit exchange studies using fluorescence resonance energy transfer show that the mutant protein forms mixed oligomers with the wild-type protein. The mutant protein is more susceptible to thermal aggregation, whereas mixed oligomer formation leads to a decreased propensity to aggregate. Co-expression of wild-type alphaA-crystallin with G98R alphaA-crystallin in E. coli rescues the mutant alphaA-crystallin from formation of inclusion bodies. These observations may underlie the molecular basis for the presenile onset, not congenital cataract, in spite of severe folding defect and aggregation of the mutant. Our study shows that the mixed oligomers of wild-type and G98R alphaA-crystallin exhibit properties dominated by those of the mutant protein in structural aspects, oligomeric size, urea-induced unfolding and, more importantly, the chaperone activity, which may provide the molecular basis for presenile cataract formation in affected individuals.
J Mol Biol 2007 Nov 09
PMID:Mixed oligomer formation between human alphaA-crystallin and its cataract-causing G98R mutant: structural, stability and functional differences. 1790 Jun 21

Human pathologies often originate from molecular disorders. Therefore, imaging technology as one of the bases for the identification and understanding of pathologies must provide views of single molecules at subnanometer resolution. Membrane proteins mediate many of life's most important processes, and their malfunction is often lethal or leads to severe disease. The membrane proteins aquaporin-0 (AQP0) and connexons form junctional microdomains between healthy lens core cells in which AQP0 form square arrays surrounded by connexons. Malfunction of both proteins results in the formation of cataract. We have used high-resolution atomic force microscopy (AFM) to image junctional microdomains in membranes from an individual human eye lens with senile cataract. Images at subnanometer resolution report individual helix-connecting loops of four amino acid residues on the AQP0 surface. We describe the supramolecular assembly and the conformational state of AQP0 in junctional microdomains, where a mixture of truncated junctional and full-length water channel AQP0 form square arrays. Imaging of microdomain borders revealed individual AQP0 tetramers and no associated connexon, indicating a lack of metabolite transport, waste accumulation, and enlarged regions of non-adhering membranes, causing cataract in this individual. This first high-resolution view of the membrane of this pathological human tissue provides insights into cataract pathology at the single membrane protein level, and indicates the power of the AFM as a future tool in medical imaging at subnanometer resolution.
J Mol Biol 2007 Nov 16
PMID:Human cataract lens membrane at subnanometer resolution. 1792 Jun 25

The expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) were studied in the conjunctiva of diabetic patients with and without retinopathy. All patients underwent a complete ophthalmic examination including ocular fundus and retinal fluorescein angiography. The indirect immunoperoxidase method was performed on 15 normal conjunctivas taken during cataract surgery (group 1), on 40 eyes of 40 patients with type 2 diabetes without diabetic retinopathy (DR) (group 2) and 13 eyes of 13 patients with DR (group 3). ICAM-1 and VCAM-1 are located in epithelial cells, vascular endothelial cells and in stromal cells. Our results show a statistically significant increase in the immunohistochemical expression of these proteins in the conjunctiva of diabetic patients with and without DR in comparison with normal conjunctiva (P = 0.001). Noteworthy, ICAM-1 and VCAM-1 are upregulated in the conjunctiva of diabetic patients with and without retinopathy, reflecting the inflammatory nature of this condition and suggesting a possible role for these mediators in the pathogenesis of diabetic microangiopathy.
J Mol Histol 2008 Apr
PMID:Adhesion molecules (ICAM-1 and VCAM-1) and diabetic retinopathy in type 2 diabetes. 1816 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>