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Copa mutations

Yuan Yao, Sukhbold Enkhtsetseg, Ingvild Odsbu, Lifei Fan, Morigen Morigen
BACKGROUND: The MiniR1-1 plasmid is a derivative of the R1 plasmid, a low copy cloning vector. RESULTS: Nucleotide sequencing analysis shows that the MiniR1-1 plasmid is a 6316 bp circular double-stranded DNA molecule with an oriR1 (origin for replication). The plasmid carries the repA, tap, copA and bla genes, and genes for ORF1 and ORF2. MiniR1-1 contains eight DnaA-binding sites (DnaA-boxes). DnaA-box1 is in the oriR1 region and fully matched to the DnaA-box consensus sequence, and DnaA-box8, with one mismatch, is close to the copA gene...
April 3, 2018: BMC Microbiology
Nadia Nathan, Keren Borensztajn, Annick Clement
PURPOSE OF REVIEW: Interstitial lung disease (ILD) in children (chILD) is an umbrella term for a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and implicates genetic contributors. The purpose of this review is to provide updated information on the molecular defects associated with the development of chILD. RECENT FINDINGS: Currently, the main mutations are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, and NKX2-1...
May 2018: Current Opinion in Pulmonary Medicine
Yoshimi Ohashi, Mutsumi Okamura, Ryohei Katayama, Siyang Fang, Saki Tsutsui, Akinobu Akatsuka, Mingde Shan, Hyeong-Wook Choi, Naoya Fujita, Kentaro Yoshimatsu, Isamu Shiina, Takao Yamori, Shingo Dan
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression...
January 5, 2018: Oncotarget
Yuuki Obata, Keita Horikawa, Isamu Shiina, Tsuyoshi Takahashi, Takatsugu Murata, Yasutaka Tasaki, Kyohei Suzuki, Keita Yonekura, Hiroyasu Esumi, Toshirou Nishida, Ryo Abe
Most gastrointestinal stromal tumours (GISTs) are caused by constitutively active mutations in Kit tyrosine kinase. The drug imatinib, a specific Kit inhibitor, improves the prognosis of metastatic GIST patients, but these patients become resistant to the drug by acquiring secondary mutations in the Kit kinase domain. We recently reported that a Kit mutant causes oncogenic signals only on the Golgi apparatus in GISTs. In this study, we show that in GIST, 2-methylcoprophilinamide (M-COPA, also known as "AMF-26"), an inhibitor of biosynthetic protein trafficking from the endoplasmic reticulum (ER) to the Golgi, suppresses Kit autophosphorylation at Y703/Y721/Y730/Y936, resulting in blockade of oncogenic signalling...
February 28, 2018: Cancer Letters
Brynjar O Jensson, Sif Hansdottir, Gudny A Arnadottir, Gerald Sulem, Ragnar P Kristjansson, Asmundur Oddsson, Stefania Benonisdottir, Hakon Jonsson, Agnar Helgason, Jona Saemundsdottir, Olafur T Magnusson, Gisli Masson, Gudmundur A Thorisson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Ingileif Jonsdottir, Vigdis Petursdottir, Jon R Kristinsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Reynir Arngrimsson, Patrick Sulem, Gunnar Gudmundsson, Kari Stefansson
BACKGROUND: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. CASE PRESENTATION: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis...
November 14, 2017: BMC Medical Genetics
Stefano Volpi, Jessica Tsui, Marcello Mariani, Claudia Pastorino, Roberta Caorsi, Oliviero Sacco, Angelo Ravelli, Anthony K Shum, Marco Gattorno, Paolo Picco
Mutations of the COPA gene cause an immune dysregulatory disease characterised by polyarticular arthritis and progressive interstitial lung disease with pulmonary haemorrhages. We report the case of a young girl that presented at age 3 with polyarticular arthritis, chronic cough and high titer rheumatoid factor. Radiologic imaging showed interstitial lung disease with tree-in-a-bud nodules and air-filled cysts. Targeted genetic analysis of COPA gene showed the reported c.698G>A mutation. The patient was lost to follow up for 3years during which therapy was discontinued with the development of joint damage and deformities...
February 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
E Bourneuf, P Otz, H Pausch, V Jagannathan, P Michot, C Grohs, G Piton, S Ammermüller, M-C Deloche, S Fritz, H Leclerc, C Péchoux, A Boukadiri, C Hozé, R Saintilan, F Créchet, M Mosca, D Segelke, F Guillaume, S Bouet, A Baur, A Vasilescu, L Genestout, A Thomas, A Allais-Bonnet, D Rocha, M-A Colle, C Klopp, D Esquerré, C Wurmser, K Flisikowski, H Schwarzenbacher, J Burgstaller, M Brügmann, E Dietschi, N Rudolph, M Freick, S Barbey, G Fayolle, C Danchin-Burge, L Schibler, B Bed'Hom, B J Hayes, H D Daetwyler, R Fries, D Boichard, D Pin, C Drögemüller, A Capitan
In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci...
September 13, 2017: Scientific Reports
Yasushi Hara, Yuuki Obata, Keita Horikawa, Yasutaka Tasaki, Kyohei Suzuki, Takatsugu Murata, Isamu Shiina, Ryo Abe
Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib...
2017: PloS One
Lisa-Marie Bittner, Alexander Kraus, Sina Schäkermann, Franz Narberhaus
The trace element copper serves as cofactor for many enzymes but is toxic at elevated concentrations. In bacteria, the intracellular copper level is maintained by copper efflux systems including the Cue system controlled by the transcription factor CueR. CueR, a member of the MerR family, forms homodimers, and binds monovalent copper ions with high affinity. It activates transcription of the copper tolerance genes copA and cueO via a conserved DNA-distortion mechanism. The mechanism how CueR-induced transcription is turned off is not fully understood...
2017: Frontiers in Molecular Biosciences
Begoña Águila-Clares, Luisa F Castiblanco, José Miguel Quesada, Ramón Penyalver, Juan Carbonell, María M López, Ester Marco-Noales, George W Sundin
Fire blight is a devastating plant disease caused by the bacterium Erwinia amylovora, and its control is frequently based on the use of copper-based compounds whose mechanisms of action are not well known. Consequently, in this article, we investigate the response of E. amylovora to copper shock by a whole-genome microarray approach. Transcriptional analyses showed that, in the presence of copper, 23 genes were increased in expression; these genes were classified mainly into the transport and stress functional categories...
January 2018: Molecular Plant Pathology
A M Martínez-Montes, A Fernández, D Pérez-Montarelo, E Alves, R M Benítez, Y Nuñez, C Óvilo, N Ibañez-Escriche, J M Folch, A I Fernández
RNA-Seq technology is widely used in quantitative gene expression studies and identification of non-annotated transcripts. However this technology also can be used for polymorphism detection and RNA editing in transcribed regions in an efficient and cost-effective way. This study used SNP data from an RNA-Seq assay to identify genes and mutations underlying production trait variations in an experimental pig population. The hypothalamic and hepatic transcriptomes of nine extreme animals for growth and fatness from an (Iberian × Landrace) × Landrace backcross were analyzed by RNA-Seq methodology, and SNP calling was conducted...
April 2017: Animal Genetics
Z B Mei, C Y Duan, C B Li, L Cui, S Ogino
BACKGROUND: Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC. MATERIALS AND METHODS: Electronic databases were searched from inception through May 2015...
October 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Kate El Bouzidi, Dami Collier, Eleni Nastouli, Andrew J Copas, Robert F Miller, Ravindra K Gupta
BACKGROUND: Clinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied. METHODS: An observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports...
November 2016: Journal of Antimicrobial Chemotherapy
Timothy J Vece, Levi B Watkin, Sarah Nicholas, Debra Canter, Michael C Braun, R Paul Guillerman, Karen W Eldin, Grant Bertolet, Scott McKinley, Marietta de Guzman, Lisa Forbes, Ivan Chinn, Jordan S Orange
Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: "Copa syndrome". Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER)...
May 2016: Journal of Clinical Immunology
María Celestina Sánchez-Sutil, Francisco Javier Marcos-Torres, Juana Pérez, María Ruiz-González, Elena García-Bravo, Marina Martínez-Cayuela, Nuria Gómez-Santos, Aurelio Moraleda-Muñoz, José Muñoz-Dorado
Myxococcus xanthus CorSR is a two-component system responsible for maintaining the response of this bacterium to copper. In the presence of this metal it upregulates, among others, the genes encoding the multicopper oxidase CuoA and the P1B -ATPase CopA. Dissection of the periplasmic sensor domain of the histidine kinase CorS by the analysis of a series of in-frame deletion mutants generated in this portion of the protein has revealed that copper sensing requires a region of 28 residues in the N terminus and another region of nine residues in the C terminus...
June 2016: Environmental Microbiology Reports
Isabelle Melki, Yanick J Crow
Fuelled by the on-going sequencing revolution, the last two years have seen a number of exciting discoveries relating to monogenic disorders predisposing to autoimmunity that provide new insights into the function of the human immune system. Here we discuss a selection of these diseases due to mutations in PRKCD, CTLA4, STAT3, IFIH1, TMEM173 and COPA.
December 2015: Current Opinion in Immunology
Adriana Almeida de Jesus, Raphaela Goldbach-Mansky
PURPOSE OF REVIEW: We review newly discovered monogenic immune-dysregulatory disorders that were reported in Pubmed over the last year. RECENT FINDINGS: Fourteen novel monogenic immune-dysregulatory disorders that present with innate and acquired/adaptive immune dysregulation and inflammatory clinical phenotypes were identified. These include autosomal-dominant gain-of function mutations in viral innate immune sensors or their adaptors, TMEM173/STING IFIH1/MDA5 and DDX58/RIG-I that cause complex clinical syndromes distinct from IL-1-mediated diseases and present with a chronic type I interferon (IFN Type I) signature in peripheral blood...
September 2015: Current Opinion in Rheumatology
Ben Dorshorst, Corneliu Henegar, Xiaoping Liao, Markus Sällman Almén, Carl-Johan Rubin, Shosuke Ito, Kazumasa Wakamatsu, Paul Stothard, Brian Van Doormaal, Graham Plastow, Gregory S Barsh, Leif Andersson
Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle...
2015: PloS One
Kamna Singh, Dilani B Senadheera, Céline M Lévesque, Dennis G Cvitkovitch
UNLABELLED: In bacteria, copper homeostasis is closely monitored to ensure proper cellular functions while avoiding cell damage. Most Gram-positive bacteria utilize the copYABZ operon for copper homeostasis, where copA and copB encode copper-transporting P-type ATPases, whereas copY and copZ regulate the expression of the cop operon. Streptococcus mutans is a biofilm-forming oral pathogen that harbors a putative copper-transporting copYAZ operon. Here, we characterized the role of copYAZ operon in the physiology of S...
August 1, 2015: Journal of Bacteriology
Levi B Watkin, Birthe Jessen, Wojciech Wiszniewski, Timothy J Vece, Max Jan, Youbao Sha, Maike Thamsen, Regie L P Santos-Cortez, Kwanghyuk Lee, Tomasz Gambin, Lisa R Forbes, Christopher S Law, Asbjørg Stray-Pedersen, Mickie H Cheng, Emily M Mace, Mark S Anderson, Dongfang Liu, Ling Fung Tang, Sarah K Nicholas, Karen Nahmod, George Makedonas, Debra L Canter, Pui-Yan Kwok, John Hicks, Kirk D Jones, Samantha Penney, Shalini N Jhangiani, Michael D Rosenblum, Sharon D Dell, Michael R Waterfield, Feroz R Papa, Donna M Muzny, Noah Zaitlen, Suzanne M Leal, Claudia Gonzaga-Jauregui, Eric Boerwinkle, N Tony Eissa, Richard A Gibbs, James R Lupski, Jordan S Orange, Anthony K Shum
Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport...
June 2015: Nature Genetics
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