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  • 1
    Abstract: The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.
    Type of Publication: Journal article published
    PubMed ID: 28120103
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  • 2
    Abstract: In solid tumours millions of cells are shed into the blood circulation each day. Only a subset of these circulating tumour cells (CTCs) survive, many of them presumable because of their potential to form multi-cellular clusters also named spheroids. Tumour cells within these spheroids are protected from anoikis, which allows them to metastasize to distant organs or re-seed at the primary site. We used spheroid cultures of head and neck squamous cell carcinoma (HNSCC) cell lines as a model for such CTC clusters for determining the role of the epidermal growth factor receptor (EGFR) in cluster formation ability and cell survival after detachment from the extra-cellular matrix. The HNSCC cell lines FaDu, SCC-9 and UT-SCC-9 (UT-SCC-9P) as well as its cetuximab (CTX)-resistant sub-clone (UT-SCC-9R) were forced to grow in an anchorage-independent manner by coating culture dishes with the anti-adhesive polymer poly-2-hydroxyethylmethacrylate (poly-HEMA). The extent of apoptosis, clonogenic survival and EGFR signalling under such culture conditions was evaluated. The potential of spheroid formation in suspension culture was found to be positively correlated with the proliferation rate of HNSCC cell lines as well as their basal EGFR expression levels. CTX and gefitinib blocked, whereas the addition of EGFR ligands promoted anchorage-independent cell survival and spheroid formation. Increased spheroid formation and growth were associated with persistent activation of EGFR and its downstream signalling component (MAPK/ERK). Importantly, HNSCC cells derived from spheroid cultures retained their clonogenic potential in the absence of cell-matrix contact. Addition of CTX under these conditions strongly inhibited colony formation in CTX-sensitive cell lines but not their resistant subclones. Altogether, EGFR activation was identified as crucial factor for anchorage-independent survival of HNSCC cells. Targeting EGFR in CTC cluster formation might represent an attractive anti-metastatic treatment approach in HNSCC.
    Type of Publication: Journal article published
    PubMed ID: 27643613
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  • 3
    Publication Date: 2013-11-12
    Description: Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha1 subunit of soluble guanylyl cyclase (alpha1-sGC), and CCT7 encodes CCTeta, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce alpha1-sGC as well as beta1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in alpha1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erdmann, Jeanette -- Stark, Klaus -- Esslinger, Ulrike B -- Rumpf, Philipp Moritz -- Koesling, Doris -- de Wit, Cor -- Kaiser, Frank J -- Braunholz, Diana -- Medack, Anja -- Fischer, Marcus -- Zimmermann, Martina E -- Tennstedt, Stephanie -- Graf, Elisabeth -- Eck, Sebastian -- Aherrahrou, Zouhair -- Nahrstaedt, Janja -- Willenborg, Christina -- Bruse, Petra -- Braenne, Ingrid -- Nothen, Markus M -- Hofmann, Per -- Braund, Peter S -- Mergia, Evanthia -- Reinhard, Wibke -- Burgdorf, Christof -- Schreiber, Stefan -- Balmforth, Anthony J -- Hall, Alistair S -- Bertram, Lars -- Steinhagen-Thiessen, Elisabeth -- Li, Shu-Chen -- Marz, Winfried -- Reilly, Muredach -- Kathiresan, Sekar -- McPherson, Ruth -- Walter, Ulrich -- CARDIoGRAM -- Ott, Jurg -- Samani, Nilesh J -- Strom, Tim M -- Meitinger, Thomas -- Hengstenberg, Christian -- Schunkert, Heribert -- British Heart Foundation/United Kingdom -- England -- Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S937 Paris, France [3]. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany [3]. ; Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Physiologie, Universitat zu Lubeck, 23562 Lubeck, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany. ; 1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland. ; 1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany. ; Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany. ; Institute of Clinical Molecular Biology, Christian-Albrecht-Universitat, 24105 Kiel, Germany. ; Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Charite Research Group on Geriatrics, Charite-Universitatsmedizin, 10117 Berlin, Germany. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany [2] Department of Psychology, TU Dresden, 01062 Dresden, Germany. ; 1] Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria [3] Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. ; The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02215, USA. ; University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada. ; 1] Centrum fur Thrombose und Hamostase (CTH), Universitatsmedizin Mainz, 55131 Mainz, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany. ; 1] Institute of Psychology, Chinese Academy of Sciences, Beijing 100864, China [2] Laboratory of Statistical Genetics, Rockefeller University, New York 10065, USA. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24213632" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chaperonin Containing TCP-1/genetics/metabolism ; Cyclic GMP/metabolism ; Disease Susceptibility/*metabolism ; Exome/genetics ; Female ; Genetic Predisposition to Disease ; Guanylate Cyclase/deficiency/genetics/metabolism ; HEK293 Cells ; Humans ; Male ; Mice ; Mutation/genetics ; Myocardial Infarction/genetics/*metabolism/physiopathology ; Nitric Oxide/*metabolism ; Pedigree ; Platelet Activation ; Receptors, Cytoplasmic and Nuclear/deficiency/genetics/metabolism ; Reproducibility of Results ; *Signal Transduction ; Solubility ; Thrombosis/metabolism ; Vasodilation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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