Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Duchenne/Becker muscular dystrophy (DMD/BMD) is a severe X-linked myopathy. In 65% of the patients, the mutations responsible for the disease are macrodeletions in the dystrophin-encoding gene that can be identified with multiplex polymerase chain reaction (PCR) technology. We developed a method for quantitative PCR analysis of deletion carriers involving the use of phosphorimager-based scanning of radioactive-labelled PCR products. We calculated the ratios between the areas of two peaks, one corresponding to the deleted segments to be analysed and the other taken as a reference. In carriers, these ratios (R value) were always about half those obtained in normal females. The final diagnostic result, the diagnostic index (DI), is the ratio of the R values between the propositus and a normal subject. We also assessed the variability of each step of the procedure and the overall variability of the DI value, thus obtaining cut-off values that completely discriminated BMD/DMD deletion carriers from normal females. We were also able to classify, as either 'carrier' or 'normal', several females whose status was not identified with linkage analysis.
Mol Cell Probes 1996 Apr
PMID:A quantitative polymerase chain reaction (PCR) assay completely discriminates between Duchenne and Becker muscular dystrophy deletion carriers and normal females. 873 97

VMD is a molecular graphics program designed for the display and analysis of molecular assemblies, in particular biopolymers such as proteins and nucleic acids. VMD can simultaneously display any number of structures using a wide variety of rendering styles and coloring methods. Molecules are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resolution raster images of displayed molecules may be produced by generating input scripts for use by a number of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate molecular dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biology, which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs. VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
J Mol Graph 1996 Feb
PMID:VMD: visual molecular dynamics. 874 70

Recently, a significant activity of inducible nitric oxide synthase (iNOS) has been reported in biopsies from failing hearts due to idiopathic dilated cardiomyopathy (IDC). Thus, a potential pathophysiological role of iNOS in IDC has been stated. In order to investigate, whether iNOS expression is of pathophysiological relevance in human heart failure, we measured iNOS protein expression and cGMP content in left ventricular myocardium from non-failing and failing human hearts. Immunoblot analysis revealed iNOS protein expression in four out of six failing hearts from septic patients, whereas no iNOS-protein expression was detected in either non-failing human hearts (n = 6) or failing hearts due to IDC (n = 9), ischemic heart disease (IHD, n = 7), Becker muscular dystrophy (BMD, n = 2) and mitoxantrone-induced toxic cardiomyopathy TCM, n = 1). cGMP content was increased by 130% in septic hearts, whereas there was no cGMP increase in hearts with IDC. IHD and BMD compared to non-failing hearts. We conclude, that the induction of iNOS may play a role in contractile dysfunction observed in septic shock, but is unlikely to be of major pathophysiological importance in end-stage heart failure due to IDC, IHD, BMD and TCM.
J Mol Cell Cardiol 1996 Jan
PMID:Expression of inducible nitric oxide synthase in failing and non-failing human heart. 874 24

Mutations in the dystrophin gene are responsible for Duchenne and Becker muscular dystrophy (DMD/BMD). Studies of dystrophin expression and function have benefited from use of the mdx mouse, an animal model for DMD/BMD. Here we characterized mutations in three additional strains of mdx mice, the mdx2cv, mdx4cv and mdx5cv alleles. The mutation in the mdx2cv mouse was found to be a single base change in the splice acceptor sequence of dystrophin intron 42. This mutation leads to a complex pattern of aberrant splicing that generates multiple transcripts, none of which preserve the normal open reading frame. In the mdx5cv allele, the dystrophin mRNA contains a 53 bp deletion of sequences from exon 10. Analysis of the genomic DNA uncovered a single A to T transversion in exon 10. Although this base change does not alter the encoded amino acid, a new splice donor was created (GTGAG) that generates a frameshifting deletion in the processed mRNA. In the mdx4cv allele, direct sequencing revealed a C to T transition in exon 53, creating an ochre codon (CAA to TAA). The differential location of these mutations relative to the seven known dystrophin promoters results in a series of mdx mouse mutants that differ in their repertoire of isoform expression, such that these mice should be useful for studies of dystrophin expression and function. The mdx4cv and mdx5cv strains may be of additional use in gene transfer studies due to their low frequency of mutation reversion.
Hum Mol Genet 1996 Aug
PMID:Differential expression of dystrophin isoforms in strains of mdx mice with different mutations. 884 34

The activity of many proteins induces conformational transitions by hinge-bending, which involves the movement of relatively rigid parts of a protein about flexible joints. We present an algorithm to identify and visualize the movements of rigid domains about common hinges in proteins. In comparing two structures, the method partitions a protein into domains of preserved geometry. The domains are extracted by an adaptive selection procedure using least-squares fitting. The user can maintain the spatial connectivity of the domains and filter significant structural differences (domain movements) from noise in the compared sets of atomic coordinates. The algorithm subsequently characterizes the relative movements of the found domains by effective rotation axes (hinges). The method is applied to several known instances of domain movements in protein structures, namely, in lactoferrin, hexokinase, actin, the extracellular domains of human tissue factor, and the receptor of human growth factor. The results are visualized with the molecular graphics package VMD (Humphrey et al., J. Mol. Graphics 14(1):33-38, 1996). Applications of the algorithm to the analysis of conformational changes in proteins and to biomolecular docking are discussed.
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PMID:Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates. 929 63

Differential display (DD) is a powerful instrument to detect differences in gene expression of malignant and normal cells. An optimized silver staining protocol was used to compare mRNA expression of keratinocytes and squamous cell carcinoma cells of the head and neck. Optimal concentration for upstream and downstream primer was 0.2 microM. Best primer concentrations for reamplification were between 40 and 60 pM. With this optimized protocol nearly 50 differentially expressed transcripts have been identified and differential display can be applied safer, easier, and faster, than by radioactive labeling.
Res Commun Mol Pathol Pharmacol 1997 Aug
PMID:Optimized differential display and reamplification parameters for silver staining. 934 36

GTPases of the Rho subfamily, i.e. Rho, Rac and Cdc42, are molecular switches in various signaling pathways. Best characterized are their functions in the regulation of the actin cytoskeleton. In neuronal cell lines they are involved in the mechanisms leading to synapse formation and plasticity. It is still unknown whether they have respective functions in the mammalian CNS. In this case, they should be present in the adult brain, especially in areas known for their synaptic remodeling. We have studied the expression of the Rho GTPases in adult rat brain with in situ hybridization and Western blot analysis. High amounts of RhoA, RhoB, Rac1 and Cdc42 mRNAs were detected in neurons of the hippocampus, i.e. in pyramidal cells of the CA1-CA4 regions as well as in granule cells of the dentate gyrus and in hilar cells. Also in cerebellum, Purkinje and granular cells expressed the four mRNAs. Strong gene expression was also found in brainstem, thalamus and neocortex. Using Western blot analysis, RhoA and Cdc42 proteins were detected in hippocampus, cerebellum, thalamus and neocortex. It is concluded that GTPases of the Rho family play a role in the regulation of cellular functions in the adult brain.
Brain Res Mol Brain Res 1997 Dec 15
PMID:Gene expression of the small GTP-binding proteins RhoA, RhoB, Rac1, and Cdc42 in adult rat brain. 949 48

This review summarizes the evolution of ideas concerning insulin signal transduction, the current information on protein ser/thr kinase cascades as signalling intermediates, and their status as participants in insulin regulation of energy metabolism. Best characterized is the Ras-MAPK pathway, whose input is crucial to cell fate decisions, but relatively dispensable in metabolic regulation. By contrast the effectors downstream of PI-3 kinase, although less well elucidated, include elements indispensable for the insulin regulation of glucose transport, glycogen and cAMP metabolism. Considerable information has accrued on PKB/cAkt, a protein kinase that interacts directly with Ptd Ins 3'OH phosphorylated lipids, as well as some of the elements further downstream, such as glycogen synthase kinase-3 and the p70 S6 kinase. Finally, some information implicates other erk pathways (e.g. such as the SAPK/JNK pathway) and Nck/cdc42-regulated PAKs (homologs of the yeast Ste 20) as participants in the cellular response to insulin. Thus insulin recruits a broad array of protein (ser/thr) kinases in its target cells to effectuate its characteristic anabolic and anticatabolic programs.
Mol Cell Biochem 1998 May
PMID:Insulin signal transduction through protein kinase cascades. 960 12

Vitelliform macular dystrophy (Best's disease) is an autosomal dominant, early-onset form of macular degeneration in which the primary defect is thought to occur at the level of the retinal pigment epithelium. Genetic linkage has mapped the disease locus to chromosome 11q12-q13.1 within a 980 kb interval flanked by markers at loci D11S4076 and uteroglobin. To identify the disease gene, we systematically characterized genes from within the critical region and analysed the coding regions for mutations in 12 patients from large multigeneration Best's disease families. Following this approach, we identified a novel gene of unknown function carrying heterozygous mutations in all 12 probands. Of these, 10 result in distinct missense mutations of amino acids that are highly conserved throughout evolution, spanning a phylogenetic distance from Caenorhabditis elegans to human, and include V9M, A10T, W24C, R25Q, R218Q, Y227N, Y227C, V235M, P297A and F305S. One deletion mutation, DeltaI295, was found in two families and segregates with the disease in both cases. Northern blot analysis reveals tissue-specific expression for this gene, exclusively in the retinal pigment epithelium. In conclusion, our data provide strong evidence that mutations in the gene that we have identified cause Best's disease.
Hum Mol Genet 1998 Sep
PMID:Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). 970 Feb 9

The effects of regulatory amounts of Ca2+ on the in situ structures of troponin C (TnC) and troponin I (TnI) in whole troponin have been investigated by neutron scattering. In separate difference experiments, 97% deuterated TnC and TnI within whole troponin were studied +/-Ca2+ in 41.6% 2H2O buffers in which protonated subunits were rendered "invisible". We found that the radius of gyration (Rg) of TnI decreased by approximately 10% upon addition of regulatory Ca2+ indicating that it was significantly more compact in the presence of Ca2+. The apparent cross-sectional radius of gyration (Rc) of TnI increased by about 9% when regulatory Ca2+ was bound to TnC. Modeling studies showed that the high-Q scattering patterns of TnI could be fit by a TnI which consisted of two subdomains: one, a highly oblate ellipsoid of revolution containing about 65% of the mass and the other, a highly prolate ellipsoid of revolution consisting of about 35% of the mass. No other fits could be found with this class of models. Best fits were achieved when the axes of revolution of these ellipsoids were steeply inclined with respect to each other. Ca2+ addition decreased the center of mass separation by about 1.5 nm. The Rg of TnI, its high-Q scattering pattern, and the resultant structure were different from previous results on neutron scattering by TnI in the (+Ca2+) TnC.TnI complex. The Rg of TnC indicated that it was elongate in situ. The Rg of TnC was not sensitive to the Ca2+ occupancy of its regulatory sites. However, Rc increased upon Ca2+ addition in concert with expectations from NMR and crystallography of isolated TnC. The present observations indicate that TnI acts like a molecular switch which is controlled by smaller Ca2+-induced changes in TnC.
J Mol Biol 1998 Aug 28
PMID:The effect of regulatory Ca2+ on the in situ structures of troponin C and troponin I: a neutron scattering study. 971 May 40


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