Mutations

Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of Mutations

  • K-ra mutation
  • KRA mutation
  • acid mutation
  • activating mutation
  • adaptive mutation
  • additional mutation
  • alanine mutation
  • amino acid mutation
  • amyloidogenic mutation
  • another mutation
  • apc mutation
  • atm mutation
  • base mutation
  • beneficial mutation
  • biallelic mutation
  • braf mutation
  • braf v600e mutation
  • brafv600e mutation
  • brca mutation
  • brca1 mutation
  • brca1/2 mutation
  • brca2 gene mutation
  • brca2 mutation
  • c mutation
  • c282y mutation
  • c677t mutation
  • card15 mutation
  • carrying mutation
  • catenin mutation
  • causal mutation
  • causative mutation
  • cdkn2a mutation
  • cell mutation
  • cftr gene mutation
  • cftr mutation
  • channel mutation
  • chromosomal mutation
  • codon mutation
  • col7a1 mutation
  • common mutation
  • compensatory mutation
  • complex mutation
  • compound heterozygous mutation
  • constitutional mutation
  • core promoter mutation
  • ctnnb1 mutation
  • cysteine mutation
  • de novo mutation
  • defined mutation
  • deleterious mutation
  • deletion mutation
  • detectable mutation
  • detected mutation
  • different mutation
  • disease mutation
  • disease-associated mutation
  • disease-causing mutation
  • distinct mutation
  • dna mutation
  • domain mutation
  • dominant mutation
  • double mutation
  • duplication mutation
  • egfr mutation
  • epidermal growth factor receptor mutation
  • escape mutation
  • expansion mutation
  • factor receptor mutation
  • factor v leiden mutation
  • fgfr3 mutation
  • filaggrin mutation
  • first mutation
  • flg mutation
  • flt3 mutation
  • founder mutation
  • frame shift mutation
  • frame-shift mutation
  • frameshift mutation
  • frequent mutation
  • full mutation
  • function mutation
  • functional mutation
  • g mutation
  • g143a mutation
  • g2019s mutation
  • g20210a mutation
  • gain-of-function mutation
  • gch1 mutation
  • gene mutation
  • genetic mutation
  • germ-line mutation
  • germline mutation
  • gjb2 mutation
  • gnas1 mutation
  • growth factor receptor mutation
  • h63d mutation
  • hbv mutation
  • heterozygous missense mutation
  • heterozygous mutation
  • heterozygous point mutation
  • hfe mutation
  • homozygous missense mutation
  • homozygous mutation
  • homozygous nonsense mutation
  • hprt mutation
  • hrpt2 mutation
  • human mutation
  • hypomorphic mutation
  • i mutation
  • identified mutation
  • inactivating mutation
  • independent mutation
  • individual mutation
  • induced mutation
  • inherited mutation
  • insertion mutation
  • insertional mutation
  • intronic mutation
  • jak2 mutation
  • jak2 v617f mutation
  • k-ra mutation
  • kdr mutation
  • kinase mutation
  • kit mutation
  • knockout mutation
  • leiden mutation
  • lethal mutation
  • loss-of-function mutation
  • lrrk2 mutation
  • many mutation
  • mapt mutation
  • mecp2 mutation
  • men1 germline mutation
  • missense mutation
  • mitochondrial dna mutation
  • mitochondrial mutation
  • mlh1 mutation
  • mmr gene mutation
  • msh2 mutation
  • msh6 mutation
  • mtdna mutation
  • mthfr mutation
  • multiple mutation
  • neutral mutation
  • new mutation
  • nf1 mutation
  • nod2 mutation
  • nonsense mutation
  • novel deletion mutation
  • novel frameshift mutation
  • novel homozygous mutation
  • novel missense mutation
  • novel mutation
  • novel nonsense mutation
  • novel point mutation
  • novel splice site mutation
  • novo mutation
  • npm1 mutation
  • nucleotide mutation
  • null mutation
  • numerous mutation
  • of mutation
  • oncogene mutation
  • oncogenic mutation
  • one missense mutation
  • one mutation
  • other missense mutation
  • other mutation
  • parkin mutation
  • particular mutation
  • pathogenic mutation
  • pathological mutation
  • pdgfra mutation
  • pgrn mutation
  • phox2b mutation
  • point mutation
  • polymerase mutation
  • precore mutation
  • prevalent mutation
  • promoter mutation
  • prothrombin g20210a mutation
  • prothrombin mutation
  • ps1 mutation
  • pten mutation
  • ptpn11 mutation
  • random mutation
  • rare mutation
  • ras gene mutation
  • ras mutation
  • receptor mutation
  • recessive mutation
  • recurrent mutation
  • regulatory mutation
  • relevant mutation
  • reported mutation
  • resistance mutation
  • resistant mutation
  • ret mutation
  • reverse mutation
  • ryr1 mutation
  • same mutation
  • scn5a mutation
  • second mutation
  • second-site mutation
  • sequence mutation
  • several mutation
  • severe mutation
  • shift mutation
  • significant mutation
  • silent mutation
  • similar mutation
  • single base mutation
  • single gene mutation
  • single mutation
  • single nucleotide mutation
  • single point mutation
  • site mutation
  • sod1 mutation
  • sodium channel mutation
  • somatic mutation
  • specific mutation
  • splice mutation
  • splice site mutation
  • splice-site mutation
  • splicing mutation
  • spontaneous mutation
  • stop mutation
  • structural mutation
  • substitution mutation
  • surface mutation
  • synonymous mutation
  • tandem mutation
  • target-site mutation
  • targeted mutation
  • thalassemia mutation
  • thrombophilic gene mutation
  • transition mutation
  • triple mutation
  • truncating mutation
  • unique mutation
  • v leiden mutation
  • v600e mutation
  • v617f mutation
  • variety of mutation
  • various mutation
  • vivo mutation
  • x mutation

  • Terms modified by Mutations

  • mutation alone
  • mutation analysis
  • mutation carrier
  • mutation data
  • mutation database
  • mutation detectable
  • mutation detection
  • mutation detection rate
  • mutation detection strategy
  • mutation effects
  • mutation event
  • mutation frequency
  • mutation lead
  • mutation leading
  • mutation load
  • mutation model
  • mutation only
  • mutation pattern
  • mutation probability
  • mutation profile
  • mutation rate
  • mutation scanning
  • mutation screening
  • mutation screening methods
  • mutation site
  • mutation spectrum
  • mutation status
  • mutation studies
  • mutation system
  • mutation testing
  • mutation type

  • Selected Abstracts


    PEUTZ-JEGHERS SYNDROME ASSOCIATED WITH RENAL AND GASTRIC CANCER THAT DEMONSTRATED AN STK11 MISSENSE MUTATION

    DIGESTIVE ENDOSCOPY, Issue 4 2006
    Hiromi Kataoka
    A 75-year-old male was admitted to the gastroenterology unit of Nagoya City University Hospital due to epigastralgia after surgical treatment for right renal cancer. Endoscopy revealed advanced type 1 gastric cancer in the corpus of the stomach and multiple polypoid lesions in the stomach and duodenum. X-ray examination of the small intestine using barium showed multiple polyps in the upper jejunum. Faint pigmentation on the palm was also detected. Peutz-Jeghers syndrome (PJS) was diagnosed, despite a lack of family history. Total gastrectomy, resection of part of the upper jejunum and intraoperative endoscopic polypectomy of duodenal polyps was performed. This is the second reported case of PJS associated with renal cancer. We also detected a missense mutation in the tumor suppressor gene STK11 that, when mutated, is causative for PJS. [source]


    DIFFERENTIATION AMONG POPULATIONS WITH MIGRATION, MUTATION, AND DRIFT: IMPLICATIONS FOR GENETIC INFERENCE

    EVOLUTION, Issue 1 2006
    Seongho Song
    Abstract Populations may become differentiated from one another as a result of genetic drift. The amounts and patterns of differentiation at neutral loci are determined by local population sizes, migration rates among populations, and mutation rates. We provide exact analytical expressions for the mean, variance, and covariance of a stochastic model for hierarchically structured populations subject to migration, mutation, and drift. In addition to the expected correlation in allele frequencies among populations in the same geographic region, we demonstrate that there is a substantial correlation in allele frequencies among regions at the top level of the hierarchy. We propose a hierarchical Bayesian model for inference of Wright's F -statistics in a two-level hierarchy in which we estimate the among-region correlation in allele frequencies by substituting replication across loci for replication across time. We illustrate the approach through an analysis of human microsatellite data, and we show that approaches ignoring the among-region correlation in allele frequencies underestimate the amount of genetic differentiation among major geographic population groups by approximately 30%. Finally, we discuss the implications of these results for the use and interpretation of F -statistics in evolutionary studies. [source]


    THE CONTRIBUTION OF SPONTANEOUS MUTATION TO VARIATION IN ENVIRONMENTAL RESPONSES OF ARABIDOPSIS THALIANA: RESPONSES TO LIGHT

    EVOLUTION, Issue 2 2005
    Christina M. Kavanaugh
    Abstract It has been hypothesized that new, spontaneous mutations tend to reduce fitness more severely in more stressful environments. To address this hypothesis, we grew plants representing 20 Arabidopsis thaliana mutationaccumulation (M-A) lines, advanced to generation 17, and their progenitor, in differing light conditions. The experiment was conducted in a greenhouse, and two treatments were used: full sun and shade, in which influx of red light was reduced relative to far-red. The shade treatment was considered the more stressful because mean absolute fitness was lower in that treatment, though not significantly so. Plants from generation 17 of M-A developed significantly faster than those from generation 0 in both treatments. A significant interaction between generation and treatment revealed that, counter to the hypothesis, M-A lines tended to have higher fitness on average relative to the progenitor in the shaded conditions, whereas, in full sun, the two generations were similar in fitness. A secondary objective of this experiment was to characterize the contribution of new mutations to genotype x environment interaction. We did not, however, detect a significant interaction between M-A line and treatment. Plots of the line-specific enviromental responses indicate no tendency of new mutations to contribute to fitness trade-offs between environments. They also do not support a model of conditionally deleterious mutation, in which a mutatn reduces fitness only in a particular environment. These results suggest that interactions between genotype and light environment previously documented for A. thaliana are not explicable primarily as a consequence of steady input of spontaneous mutations having environment-specific effects. [source]


    DELETERIOUS MUTATION AND THE EVOLUTION OF EUSOCIALITY

    EVOLUTION, Issue 12 2002
    Joshua L. Cherry
    Abstract., Certain arguments concerning the evolution of eusociality form a classic example of the application of the principles of kin selection. These arguments center on the different degrees of relatedness of potential beneficiaries of an individual's efforts, for example a female's higher relatedness to her sisters than to her daughters in a haplodiploid system. This type of reasoning is insufficient to account for the evolution and maintainence of sexual reproduction, because parthenogenic females produce offspring that are more closely related to them than are offspring produced sexually. Among the forces invoked to explain sexual reproduction is deleterious mutation. This factor can be shown to favor eusociality as well, because siblings produced by helping carry fewer deleterious alleles on average than would offspring. The strength of this effect depends on the genomewide deleterious mutation rate, U, and on the selection coefficient, s, associated with deleterious alleles. For small s, the effect depends approximately on the product Us. This phenomenon illustrates that an assumption implicit in some analyses,that the relatedness of an individual to an actor is all that matters to its value to that actor,can fail for the evolution of eusociality as it does for the evolution of sex. [source]


    GENOCIDAL MUTATION AND THE CHALLENGE OF DEFINITION

    METAPHILOSOPHY, Issue 4 2010
    HENRY C. THERIAULT
    Abstract: The optimum definition of the term "genocide" has been hotly contested almost since the term was coined. Definitional boundaries determine which acts are covered and excluded and thus to a great extent which cases will benefit from international attention, intervention, prosecution, and reparation. The extensive legal, political, and scholarly discussions prior to this article have typically (1) assumed "genocide" to be a fixed social object and attempted to define it as precisely as possible or (2) assumed the need for a fixed convention and sought to stipulate the range of events that should be denoted by the term. Even if its meaning is a matter of convention, however, "genocide" is not a fixed object but varies by context and evolves in methods and forms over time. In fact, as relevant laws, legal interpretations, and political commitments develop, so do would-be perpetrators modify what genocide is in order to avoid political and legal consequences. This article advances an approach to a definition of "genocide" that allows even legal definitions to keep pace with this evolutionary process. [source]


    THE FITNESS EFFECT OF MUTATIONS ACROSS ENVIRONMENTS: A SURVEY IN LIGHT OF FITNESS LANDSCAPE MODELS

    EVOLUTION, Issue 12 2006
    Guillaume Martin
    Abstract The fitness effects of mutations on a given genotype are rarely constant across environments to which this genotype is more or less adapted, that is, between more or less stressful conditions. This can have important implications, especially on the evolution of ecological specialization. Stress is thought to increase the variance of mutations' fitness effects, their average, or the number of expressed mutations. Although empirical evidence is available for these three mechanisms, their relative magnitude is poorly understood. In this paper, we propose a simple approach to discriminate between these mechanisms, using a survey of empirical measures of mutation effects in contrasted environments. This survey, across various species and environments, shows that stress mainly increases the variance of mutations effects on fitness, with a much more limited impact on their average effect or on the number of expressed mutations. This pattern is consistent with a simple model in which fitness is a Gaussian function of phenotypes around an environmentally determined optimum. These results suggest that a simple, mathematically tractable landscape model may not be quantitatively as unrealistic as previously suggested. They also suggest that mutation parameter estimates may be strongly biased when measured in stressful environments. [source]


    HOW ARE DELETERIOUS MUTATIONS PURGED?

    EVOLUTION, Issue 12 2003
    DRIFT VERSUS NONRANDOM MATING
    Abstract Accumulation of deleterious mutations has important consequences for the evolution of mating systems and the persistence of small populations. It is well established that consanguineous mating can purge a part of the mutation load and that lethal mutations can also be purged in small populations. However, the efficiency of purging in natural populations, due to either consanguineous mating or to reduced population size, has been questioned. Consequences of consanguineous mating systems and small population size are often equated under "inbreeding" because both increase homozygosity, and selection is though to be more efficient against homozygous deleterious alleles. I show that two processes of purging that I call "purging by drift" and "purging by nonrandom mating" have to be distinguished. Conditions under which the two ways of purging are effective are derived. Nonrandom mating can purge deleterious mutations regardless of their dominance level, whereas only highly recessive mutations can be purged by drift. Both types of purging are limited by population size, and sharp thresholds separate domains where purging is either effective or not. The limitations derived here on the efficiency of purging are compatible with some experimental studies. Implications of these results for conservation and evolution of mating systems are discussed. [source]


    COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS

    EVOLUTION, Issue 5 2000
    Art Poon
    Abstract We have investigated the reduction of fitness caused by the fixation of new deleterious mutations in small populations within the framework of Fisher's geometrical model of adaptation. In Fisher's model, a population evolves in an n -dimensional character space with an adaptive optimum at the origin. The model allows us to investigate compensatory mutations, which restore fitness losses incurred by other mutations, in a context-dependent manner. We have conducted a moment analysis of the model, supplemented by the numerical results of computer simulations. The mean reduction of fitness (i.e., expected load) scaled to one is approximately n/(n + 2Ne), where Ne is the effective population size. The reciprocal relationship between the load and Ne implies that the fixation of deleterious mutations is unlikely to cause extinction when there is a broad scope for compensatory mutations, except in very small populations. Furthermore, the dependence of load on n implies that pleiotropy plays a large role in determining the extinction risk of small populations. Differences and similarities between our results and those of a previous study on the effects of Ne and n are explored. That the predictions of this model are qualitatively different from studies ignoring compensatory mutations implies that we must be cautious in predicting the evolutionary fate of small populations and that additional data on the nature of mutations is of critical importance. [source]


    THE FITNESS EFFECTS OF SPONTANEOUS MUTATIONS IN CAENORHABDITIS ELEGANS

    EVOLUTION, Issue 4 2000
    Larissa L. Vassilieva
    Abstract. Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity. [source]


    LIBERALIZATION OF EUROPEAN TELECOMMUNICATIONS: SECTORAL DYNAMICS AND STRUCTURAL MUTATIONS

    ANNALS OF PUBLIC AND COOPERATIVE ECONOMICS, Issue 3 2007
    Philippe BANCE
    ABSTRACT,:,This contribution intends to draw up an assessment of structural changes in the telecommunications sector impelled by the European policy of liberalization. Deep transformations with contrasted results have occurred. A strong differentiation in offer of services and a considerable fall in cost appears. After a strong growth, however, investment sharply decreased with the financial crisis. Employment has become a variable of adjustment for companies subjected to strong risks due to the economic situation. Lastly, the assertion of the universal service of telecommunications is accompanied by an important reduction of public service missions. [source]


    RELEVANT RISK FOR WOMEN WITH BRCA1 AND BRCA2 MUTATIONS

    ANZ JOURNAL OF SURGERY, Issue 5 2007
    Colin Furnival PhD, FRACS
    No abstract is available for this article. [source]


    NOVEL MITOCHONDRIAL DNA MUTATIONS ASSOCIATED WITH CHINESE FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2009
    Yan-Ling Wei
    SUMMARY 1Hypertrophic cardiomyopathy (HCM) is a genetic disorder that has a complex set of symptoms and potentially devastating consequences. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations are responsible for the development of HCM, but the mtDNA mutations appear to differ considerably among different populations and regions. 2In the present study, three families with HCM were found and investigated: one in Shandong province and two in the Chongqing region of China. The entire mtDNA genome from the 18 affected and 66 unaffected family members was sequenced directly and the mtDNA mutations were determined. 3The frequency of haplogroup M10 was significantly higher in family members with HCM (HCM group) than in unaffected family members (normal group). Three mtDNA mutations were found with a significantly higher frequency in affected individuals than in unaffected family individuals, namely G7697A in the cytochrome c oxidase subunit II gene (P < 0.0001; odds ratio (OR) 227.5; 95% confidence interval (CI) 23.6,2194.8) and T12477C (P = 0.0037; OR 5.6; 95% CI 1.8,17.6) and G13135A in the NADH dehydrogenase 5 gene (P < 0.0001; OR 26.0; 95% CI 6.9,98.3), suggesting that these mutations are probably associated with susceptibility to HCM. In addition, mitochondrial Complex I activity was markedly decreased in the HCM group, suggesting that these mutations most likely affect mitochondrial respiratory function. 4In conclusion, the results of the present study imply that mtDNA mutations G7697A, T12477C and G13135A are genetic factors that indicate a susceptibility to HCM and that could be used for the large-scale screening of genetic markers as well as the early diagnosis of HCM. [source]


    Mutagenesis of ,-tubulin cysteine residues in Saccharomyces cerevisiae: Mutation of cysteine 354 results in cold-stable microtubules

    CYTOSKELETON, Issue 2 2001
    Mohan L. Gupta Jr.
    Abstract Cysteine residues play important roles in the control of tubulin function. To determine which of the six cysteine residues in ,-tubulin are critical to tubulin function, we mutated the cysteines in Saccharomyces cerevisiae ,-tubulin individually to alanine and serine residues. Of the twelve mutations, only three produced significant effects: C12S, C354A, and C354S. The C12S mutation was lethal in the haploid, but the C12A mutation had no observable phenotype. Based on interactive views of the electron crystallographic structure of tubulin, we suggest that substitution of serine for cysteine at this position has a destabilizing effect on the interaction of tubulin with the exchangeable GTP. The two C354 mutations, although not lethal, produced dramatic effects on microtubules and cellular processes that require microtubules. The C354 mutant cells had decreased growth rates, a slowed mitosis, increased resistance to benomyl, and impaired nuclear migration and spindle assembly. The C354A mutation produced a more severe phenotype than the C354S mutation: the haploid cells had chromosome segregation defects, only 50% of cells in a culture were viable, and a significant percentage of the cells were misshapened. Cytoplasmic microtubules in the C354S and C354A cells were longer than in the control strain and spindle structures appeared shorter and thicker. Both cytoplasmic and spindle microtubules in the two C354 mutants were extremely stable to cold temperature. After 24 h at 4°C, the microtubules were still present and, in fact, very long and thick tubulin polymers had formed. Evidence exists to indicate that the C354 residue in mammalian tubulin is near the colchicine binding site and the electron crystal structure of tubulin places the residue at the interface between the ,- and ,-subunits. The sulfhydryl group is situated in a polar environment, which may explain why the alanine mutation is more severe than the serine mutation. When the C12S and the two C354 mutations were made in a diploid strain, the mutated tubulin was incorporated into microtubules and the resulting heterozygotes had phenotypes that were intermediate between those of the mutated haploids and the wild-type strains. The results suggest that the C12 and C354 residues play important roles in the structure and function of tubulin. Cell Motil. Cytoskeleton 49:67,77, 2001. © 2001 Wiley-Liss, Inc. [source]


    Mutation in the abcb7 gene causes abnormal iron and fatty acid metabolism in developing medaka fish

    DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 9 2008
    Akimitsu Miyake
    The medaka fish (Oryzias latipes) is an emerging model organism for which a variety of unique developmental mutants have now been generated. Our recent mutagenesis screening of the medaka isolated a unique mutant that develops a fatty liver at larval stages. Positional cloning identified the responsible gene as medaka abcb7. Abcb7, a mitochondrial ABC (ATP binding cassette) half-transporter, has been implicated in iron metabolism. Recently, human Abcb7 was found to be mutated in X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). The homozygous medaka mutant exhibits abnormal iron metabolism in erythrocytes and accumulation of lipid in the liver. Microarray and in situ hybridization analyses demonstrated that the expression of genes involved in iron and lipid metabolisms are both affected in the mutant liver, suggesting novel roles of Abcb7 in the development of physiologically functional liver. The medaka abcb7 mutant thus could provide insights into the pathogenesis of XLSA/A as well as the normal function of the gene. [source]


    Genotoxicity of three mouthwash products, Cepacol®, Periogard®, and Plax®, in the Drosophila wing-spot test

    ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 8 2007
    Fábio Rodrigues
    Abstract Antiseptic mouthwashes used in biofilm control are widely available in the marketplace, despite inconsistent data concerning their genetic and cellular toxicity. In the present study, we investigated the genotoxic potential of three antiseptics currently used for odontologic treatment, Cepacol® (containing cetylpyridinium chloride), Periogard® (chlorhexidine digluconate), and Plax® (triclosan). Genotoxicity was evaluated using the Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster, employing flies having normal bioactivation (the standard cross) and flies with increased cytochrome P450-dependent biotransformation capacity (the high bioactivation cross). Periogard and Plax produced negative responses in both types of flies; however, Cepacol (75 and 100%) produced positive responses in both the standard and high bioactivation assays, with the genotoxic responses mainly due to the induction of mitotic recombination. Assays performed with ethanol and cetylpirydinium chloride, two major ingredients of Cepacol, indicated that the genotoxity of the mouthwash is likely to be due to ethanol. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source]


    A New Chrna4 Mutation with Low Penetrance in Nocturnal Frontal Lobe Epilepsy

    EPILEPSIA, Issue 7 2003
    Tobias Leniger
    Summary: Purpose: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. Methods: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. Results: We report a new CHRNA4 mutation, causing a ,4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of ,4-T265I revealed an increased ACh sensitivity of the mutated receptors. ,4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation. Conclusions: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. ,4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both. [source]


    Distinct contributions of different CD40 TRAF binding sites to CD154-induced dendritic cell maturation and IL-12 secretion

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003
    Matthew
    Abstract The mechanisms by which CD40 controls the maturation and antigen presentation functions of dendritic cells (DC) remains largely undefined in this critical cell type. To examine this question, we have employed retroviral transduction of primary bone marrow-derived mouse DC. Mutation of the distinct binding sites for TNF receptor-associated factor 6 (TRAF6) and for TRAF 2, 3, and 5 in the CD40 cytoplasmic domain revealed their independent contributions to DC maturation and activation of NF-,B. In contrast, disruption of the TRAF6 but not the TRAF 2,3,5 binding site markedly decreased IL-12 p40 secretion along with p38 and JNK activation in response to CD154 stimulation. These data document a clear bifurcation of the CD40 signaling cascade in primary DC at the level of thereceptor's two distinct and autonomous TRAF binding sites, and reveal the predominant role of the TRAF6 binding site in CD40-induced pro-inflammatory cytokine production by these cells. [source]


    Mutation in hotfoot-4J mice results in retention of ,2 glutamate receptors in ER

    EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2002
    Shinji Matsuda
    Abstract The orphan glutamate receptor ,2 is selectively expressed in Purkinje cells and plays a critical role in cerebellar function. Recently, the ataxia of hotfoot-4J (ho-4J) mice was shown to be caused by a 170,amino acid deletion in the N-terminal region of ,2 receptors. To understand ,2 receptor function, we characterized these mutant receptors (,2ho) in Purkinje cells. Immunohistochemical staining showed that ,2ho receptors of the ho-4J homozygotes were abundantly expressed but localized to the Purkinje cell soma; in wild-type mice, ,2 receptors were predominantly present at distal dendrites of Purkinje cells. In addition, ,2ho receptors of the ho-4J mice were sensitive to endoglycosidase H, a finding suggesting that ,2ho receptors were not transported beyond the endoplasmic reticulum (ER) or cis -Golgi apparatus. To gain further insights into the mechanisms of this phenomenon, we characterized ,2ho receptors in transfected HEK293 cells. ,2ho receptors expressed in HEK293 cells were also sensitive to endoglycosidase H. Immunohistochemical staining showed that ,2ho receptors colocalized with proteins retained in the ER. Furthermore, ,2ho receptors were not labelled by membrane-impermeable biotinylation reagents. Coimmunoprecipitation assays showed that the intermolecular interaction of ,2ho receptors was significantly weaker than those of wild-type ,2 receptors, a finding suggesting that the ho-4J region is involved in oligomerization of ,2 receptors. Thus, ,2ho receptors were retained in the ER, probably by the quality control mechanism that detects unstable oligomers. We conclude that the absence of ,2 receptors on the cell surface by failed transport from the ER of Purkinje cells causes ataxia. [source]


    Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

    FEBS JOURNAL, Issue 18 2010
    Chen-Hsiang Shen
    The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02,1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PRV32I, PRI54M and PRL90M resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PRI50V and PRI54V structures. The PRI84V,APV complex had lost hydrophobic contacts with APV, the PRV32I,APV complex showed increased hydrophobic contacts within the hydrophobic cluster and the PRI50V complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PRI84V,APV, PRV32I,APV and PRI50V,APV were related to their reduced inhibition by APV of six-, 10- and 30-fold, respectively, relative to wild-type PR. The APV complexes were compared with the corresponding saquinavir complexes. The PR dimers had distinct rearrangements of the flaps and 80,s loops that adapt to the different P1, groups of the inhibitors, while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs. Structured digital abstract ,,MINT-7966480: HIV-1 PR (uniprotkb:P03366) and HIV-1 PR (uniprotkb:P03366) bind (MI:0407) by x-ray crystallography (MI:0114) [source]


    An estrogen receptor , suppressor, microRNA-22, is downregulated in estrogen receptor ,-positive human breast cancer cell lines and clinical samples

    FEBS JOURNAL, Issue 7 2010
    Jianhua Xiong
    Previous studies have suggested that microRNAs (miRNAs) may play important roles in tumorigenesis, but little is known about the functions of most miRNAs in cancer development. In the present study, we set up a cell-based screen using a luciferase reporter plasmid carrying the whole , 4.7 kb 3,-UTR of estrogen receptor , (ER,) mRNA cotransfected with a synthetic miRNA expression library to identify potential ER,-targeting miRNAs. Among all the miRNAs, miR-22 was found to repress robustly the luciferase signal in both HEK-293T and ER,-positive MCF-7 cells. Mutation of the target site was found to abrogate this repression effect of miR-22, whereas antagonism of endogenous miR-22 in MDA-MB-231 cells resulted in elevated reporter signals. We assessed the miR-22 expression patterns in five breast cancer cell lines and 23 clinical biopsies and revealed that there is a significant inverse association between the miR-22 levels and ER, protein expression. To evaluate the potential of miR-22 as a potential therapeutic intervention, we found that reduction of endogenous ER, protein levels and suppression of cancer cell growth could be achieved in MCF-7 cells by miR-22 overexpression in a way that can be recapitulated by the introduction of specific small interfering RNA against ER,. The phenomena can be rescued by the reintroduction of ER,. Taken together, our data indicate that miR-22 was frequently downregulated in ER,-positive human breast cancer cell lines and clinical samples. Direct involvement in the regulation of ER, may be one of the mechanisms through which miR-22 could play a pivotal role in the pathogenesis of breast cancer. [source]


    A novel N-terminal hydrophobic motif mediates constitutive degradation of serum- and glucocorticoid-induced kinase-1 by the ubiquitin,proteasome pathway

    FEBS JOURNAL, Issue 13 2006
    Agata M. Bogusz
    Serum- and glucocorticoid-induced protein kinase-1 (SGK-1) plays a critical role in regulation of the epithelial sodium channel, ENaC. SGK-1 also shares significant catalytic domain homology with protein kinase B (PKB/AKT-1) and is a downstream effector of antiapoptotic phosphoinositide 3-kinase signaling. Steady-state levels of an active SGK-1 are tightly regulated by rapid transcriptional activation and post-translational modification including phosphorylation. We show here that endogenous SGK-1 protein is polyubiquitinated and rapidly degraded by the 26S proteasome. In contrast to other rapidly degraded kinases, neither the catalytic activity of SGK-1 nor activation site phosphorylation was required for its ubiquitin modification and degradation. Instead, SGK-1 degradation required a lysine-less six-amino-acid (amino acids 19,24) hydrophobic motif (GMVAIL) within the N-terminal domain. Deletion of amino acids 19,24 significantly increased the half-life of SGK1 and prevented its ubiquitin modification. Interestingly, this minimal region was also required for the association of SGK-1 with the endoplasmic reticulum. Ubiquitin modification and degradation of SGK-1 were increasingly inhibited by the progressive mutation of six N-terminal lysine residues surrounding the GMVAIL motif. Mutation of all six lysines to arginine did not disrupt the subcellular localization of SGK-1 despite a significant decrease in ubiquitination, implying that this modification per se was not required for targeting to the endoplasmic reticulum. These results suggest that constitutive ubiquitin-mediated degradation of SGK-1 is an important mechanism regulating its biological activity. [source]


    Novel brain 14-3-3 interacting proteins involved in neurodegenerative disease

    FEBS JOURNAL, Issue 16 2005
    Shaun Mackie
    We isolated two novel 14-3-3 binding proteins using 14-3-3 , as bait in a yeast two-hybrid screen of a human brain cDNA library. One of these encoded the C-terminus of a neural specific armadillo-repeat protein, ,-catenin (neural plakophilin-related arm-repeat protein or neurojungin). ,-Catenin from brain lysates was retained on a 14-3-3 affinity column. Mutation of serine 1072 in the human protein and serine 1094 in the equivalent site in the mouse homologue (in a consensus binding motif for 14-3-3) abolished 14-3-3 binding to ,-catenin in vitro and in transfected cells. ,-catenin binds to presenilin-1, encoded by the gene most commonly mutated in familial Alzheimer's disease. The other clone was identified as the insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53). Human IRSp53 interacts with the gene product implicated in dentatorubral-pallidoluysian atrophy, an autosomal recessive disorder associated with glutamine repeat expansion of atrophin-1. [source]


    Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selection

    FEBS JOURNAL, Issue 12 2005
    Lucila I. Castro
    Class III adenylyl cyclases usually possess six highly conserved catalytic residues. Deviations in these canonical amino acids are observed in several putative adenylyl cyclase genes as apparent in several bacterial genomes. This suggests that a variety of catalytic mechanisms may actually exist. The gene Rv0386 from Mycobacterium tuberculosis codes for an adenylyl cyclase catalytic domain fused to an AAA-ATPase and a helix-turn-helix DNA-binding domain. In Rv0386, the standard substrate, adenine-defining lysine-aspartate couple is replaced by glutamine-asparagine. The recombinant adenylyl cyclase domain was active with a Vmax of 8 nmol cAMP·mg,1·min,1. Unusual for adenylyl cyclases, Rv0386 displayed 20% guanylyl cyclase side-activity with GTP as a substrate. Mutation of the glutamine-asparagine pair either to alanine residues or to the canonical lysine-aspartate consensus abolished activity. This argues for a novel mechanism of substrate selection which depends on two noncanonical residues. Data from individual and coordinated point mutations suggest a model for purine definition based on an amide switch related to that previously identified in cyclic nucleotide phosphodiesterases. [source]


    Determinants of the nucleocytoplasmic shuttling of muscle glycogen synthase

    FEBS JOURNAL, Issue 12 2005
    Emili Cid
    Muscle glycogen synthase (MGS) presents a nuclear speckled pattern in primary cultured human muscle and in 3T3-L1 cells deprived of glucose and with depleted glycogen reserves. Nuclear accumulation of the enzyme correlates inversely with cellular glycogen content. Although the glucose-induced export of MGS from the nucleus to the cytoplasm is blocked by leptomycin B, and therefore mediated by CRM1, no nuclear export signal was identified in the sequence of the protein. Deletion analysis shows that the region comprising amino acids 555,633 of human MGS, which encompasses an Arg-rich cluster involved in the allosteric activation of the enzyme by Glc6P, is crucial for its nuclear concentration and aggregation. Mutation of these Arg residues, which desensitizes the enzyme towards Glc6P, interferes with its nuclear accumulation. In contrast, the known phosphorylation sites of MGS that regulate its activity are not involved in the control of its subcellular distribution. Nuclear human MGS colocalizes with the promyelocytic leukaemia oncoprotein and p80-coilin, a marker of Cajal bodies. The subnuclear distribution of MGS is altered by incubation with transcription inhibitors. These observations suggest that, in addition to its metabolic function, MGS may participate in nuclear processes. [source]


    Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-,1 induced murine tissue inhibitor of metalloproteinases-1 gene expression

    FEBS JOURNAL, Issue 8 2005
    David A. Young
    Expression of the tissue inhibitor of metalloproteinases-1 (Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor ,1 (TGF-,1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF-,1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-,1-induced Timp-1 expression. The repression of TGF-,1-induced Timp-1 by TSA was maximal at 5 ng·mL,1, while for the superinduction of PMA-induced Timp-1 expression, the maximal dose is >,500 ng·mL,1 TSA. A further HDACi, valproic acid, did not block TGF-,1-induced Timp-1 expression, demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-,1 to induce Timp-1 expression, new protein synthesis is required, and the induction of AP-1 factors closely precedes that of Timp-1. The effects of the HDACi can be reiterated in transient transfection using Timp-1 promoter constructs. Mutation or deletion of the AP-1 motif (,59/,53) in the Timp-1 promoter diminishes PMA-induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c-Jun,/, cells, PMA still stimulates Timp-1 expression, but TSA superinduction is lost. Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Sp1 binding motif. [source]


    Site-directed mutagenesis and footprinting analysis of the interaction of the sunflower KNOX protein HAKN1 with DNA

    FEBS JOURNAL, Issue 1 2005
    Mariana F. Tioni
    The interaction of the homeodomain of the sunflower KNOX protein HAKN1 with DNA was studied by site-directed mutagenesis, hydroxyl radical footprinting and missing nucleoside experiments. Binding of HAKN1 to different oligonucleotides indicated that HAKN1 prefers the sequence TGACA (TGTCA), with changes within the GAC core more profoundly affecting the interaction. Footprinting and missing nucleoside experiments using hydroxyl radical cleavage of DNA showed that HAKN1 interacts with a 6-bp region of the strand carrying the GAC core, covering the core and nucleotides towards the 3, end. On the other strand, protection was observed along an 8-bp region, comprising two additional nucleotides complementary to those preceding the core. Changes in the residue present at position 50 produced proteins with different specificities. An I50S mutant showed a preference for TGACT, while the presence of lysine shifted the preference to TGACC, suggesting that residue 50 interacts with nucleotide(s) 3, to GAC. Mutation of Lys54,Val produced a protein with reduced affinity and relaxed specificity, able to recognize the sequence TGAAA, while the conservative change of Arg55,Lys completely abolished binding to DNA. Based on these results, we propose a model for the interaction of HAKN1 with DNA in which helix III of the homeodomain accommodates along the major groove with Arg55, Asn51, Lys54 and Ile50, establishing specific contacts with bases of the GACA sequence or their complements. This model can be extended to other KNOX proteins given the conservation of these amino acids in all members of the family. [source]


    The role of the second binding loop of the cysteine protease inhibitor, cystatin A (stefin A), in stabilizing complexes with target proteases is exerted predominantly by Leu73

    FEBS JOURNAL, Issue 22 2002
    Alona Pavlova
    The aim of this work was to elucidate the roles of individual residues within the flexible second binding loop of human cystatin A in the inhibition of cysteine proteases. Four recombinant variants of the inhibitor, each with a single mutation, L73G, P74G, Q76G or N77G, in the most exposed part of this loop were generated by PCR-based site-directed mutagenesis. The binding of these variants to papain, cathepsin L, and cathepsin B was characterized by equilibrium and kinetic methods. Mutation of Leu73 decreased the affinity for papain, cathepsin L and cathepsin B by ,,300-fold, >10-fold and ,,4000-fold, respectively. Mutation of Pro74 decreased the affinity for cathepsin B by ,,10-fold but minimally affected the affinity for the other two enzymes. Mutation of Gln76 and Asn77 did not alter the affinity of cystatin A for any of the proteases studied. The decreased affinities were caused exclusively by increased dissociation rate constants. These results show that the second binding loop of cystatin A plays a major role in stabilizing the complexes with proteases by retarding their dissociation. In contrast with cystatin B, only one amino-acid residue of the loop, Leu73, is of principal importance for this effect, Pro74 assisting to a minor extent only in the case of cathepsin B binding. The contribution of the second binding loop of cystatin A to protease binding varies with the protease, being largest, ,,45% of the total binding energy, for inhibition of cathepsin B. [source]


    Expression and characterization of active site mutants of hevamine, a chitinase from the rubber tree Hevea brasiliensis

    FEBS JOURNAL, Issue 3 2002
    Evert Bokma
    Hevamine is a chitinase from the rubber tree Hevea brasiliensis. Its active site contains Asp125, Glu127, and Tyr183, which interact with the ,1 sugar residue of the substrate. To investigate their role in catalysis, we have successfully expressed wild-type enzyme and mutants of these residues as inclusion bodies in Escherichia coli. After refolding and purification they were characterized by both structural and enzyme kinetic studies. Mutation of Tyr183 to phenylalanine produced an enzyme with a lower kcat and a slightly higher Km than the wild-type enzyme. Mutating Asp125 and Glu127 to alanine gave mutants with ,,2% residual activity. In contrast, the Asp125Asn mutant retained substantial activity, with an approximately twofold lower kcat and an approximately twofold higher Km than the wild-type enzyme. More interestingly, it showed activity to higher pH values than the other variants. The X-ray structure of the Asp125Ala/Glu127Ala double mutant soaked with chitotetraose shows that, compared with wild-type hevamine, the carbonyl oxygen atom of the N -acetyl group of the ,1 sugar residue has rotated away from the C1 atom of that residue. The combined structural and kinetic data show that Asp125,and Tyr183 contribute to catalysis by positioning the,carbonyl oxygen of the N -acetyl group near to the C1 atom. This allows the stabilization of a positively charged transient intermediate, in agreement with a previous proposal that the enzyme makes use of substrate-assisted catalysis. [source]


    Hormonal regulation of multiple promoters of the rat mitochondrial glycerol-3-phosphate dehydrogenase gene

    FEBS JOURNAL, Issue 14 2001
    Identification of a complex hormone-response element in the ubiquitous promoter B
    Rat mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is regulated by multiple promoters in a tissue-specific manner. Here, we demonstrate that thyroid hormone (3,5,3,-tri-iodo- l -thyronine) and steroid hormone but not the peroxisome proliferator clofibrate and retinoic acid stimulate the activation of the ubiquitous promoter B in a receptor-dependent manner, whereas the more tissue-restricted promoters A and C are not inducible by these hormones. Thyroid hormone action is mediated by a direct repeat +4 (DR+4) hormone-response element as identified by deletion and mutation analyses of promoter B in transient transfection analyses. The DR+4 element was able to bind to an in vitro translated thyroid hormone receptor in band-shift and supershift experiments. The hormone-response element comaps with a recognition site for the transcription factor Sp1, suggesting complex regulation of this sequence element. Mutation of this Sp1-recognition site reduces the basal promoter B activity dramatically in HepG2 and HEK293 cells in transient transfection and abolishes the binding of Sp1 in band-shift experiments. As demonstrated by Western-blot experiments, administration of tri-iodothyronine to euthyroid rats increases hepatic mGPDH protein concentrations in vivo. As it has recently been reported that human mGPDH promoter B is not regulated by tri-iodothyronine, this is the first example of a differentially tri-iodothyronine-regulated orthologous gene promoter in man and rat. [source]


    Mutation of residues in the coenzyme binding pocket of Dopa decarboxylase

    FEBS JOURNAL, Issue 10 2001
    Effects on catalytic properties
    Residues D271, H192, H302 and N300 of l -3,4-dihydroxyphenylalanine decarboxylase (DDC), a homodimeric pyridoxal 5,-phosphate (PLP) enzyme, were mutated in order to acquire information on the catalytic mechanism. These residues are potential participants in catalysis because they belong to the common PLP-binding structural motif of group I, II and III decarboxylases and other PLP enzymes, and because they are among the putative active-site residues of structural modelled rat liver DDC. The spectroscopic features of the D271E, H192Q, H302Q and N300A mutants as well as their dissociation constants for PLP suggest that substitution of each of these residues causes alteration of the state of the bound coenzyme molecule and of the conformation of aromatic amino acids, possibly in the vicinity of the active site. This supports, but does not prove, the possibility that these residues are located in the coenzyme-binding cleft. Interestingly, mutation of each residue generates an oxidative decarboxylase activity towards l -3,4-dihydroxyphenylalanine (l -Dopa), not inherent in the wild-type in aerobiosis, and reduces the nonoxidative decarboxylase activity of l -Dopa from 3- to 390-fold. The partition ratio between oxidative and nonoxidative decarboxylation ranges from 5.7 × 10,4 for N300A mutant to 946 × 10,4 for H302Q mutant. Unlike wild-type enzyme, the mutants catalyse these two reactions to the same extent either in the presence or absence of O2. In addition, all four mutants exhibit an extremely low level of the oxidative deaminase activity towards serotonin with respect to wild-type. All these findings demonstrate that although D271, H192, H302 and N300 are not essential for catalysis, mutation of these residues alters the nature of catalysis. A possible relationship among the integrity of the PLP cleft, the productive binding of O2 and the transition to a closed conformational state of DDC is discussed. [source]