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1. A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant

Author

Morange, Pierre-Emmanuel, Peiretti, Franck, Gourhant, Lenaick, Proust, Carole, Soukarieh, Omar, Pulcrano-Nicolas, Anne-Sophie, Saripella, Ganapathi-Varma, Stefanucci, Luca, Lacroix, Romaric, Ibrahim-Kosta, Manal, Lemarié, Catherine A, Frontini, Mattia, Alessi, Marie-Christine, Trégouët, David-Alexandre, Couturaud, Francis, Morange, Pierre-Emmanuel [0000-0002-9065-722X], Peiretti, Franck [0000-0001-7198-0534], Gourhant, Lenaick [0000-0002-5761-8480], Soukarieh, Omar [0000-0003-4923-4353], Saripella, Ganapathi-Varma [0000-0003-3504-9333], Stefanucci, Luca [0000-0002-4352-1151], Lemarié, Catherine A [0000-0002-3897-4287], Frontini, Mattia [0000-0001-8074-6299], Alessi, Marie-Christine [0000-0003-3927-5792], Trégouët, David-Alexandre [0000-0001-9084-7800], Couturaud, Francis [0000-0002-1855-8032], Apollo - University of Cambridge Repository, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, HAL Sorbonne Université 5

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Physiology, QH426-470, Biochemistry, Vascular Medicine, Epithelium, Sequencing techniques, Animal Cells, Risk Factors, Medicine and Health Sciences, Thrombophilia, Venous Thrombosis, RNA sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Venous Thromboembolism, Small interfering RNA, Middle Aged, Body Fluids, Pedigree, Nucleic acids, Blood, Female, Anatomy, Cellular Types, Microtubule-Associated Proteins, Medical Genetics, Research Article, Adult, Lipoproteins, Protein Serine-Threonine Kinases, Transfection, Research and Analysis Methods, Blood Plasma, Thromboembolism, Plasminogen Activator Inhibitor 1, Exome Sequencing, Genetics, Humans, Genetic Predisposition to Disease, Non-coding RNA, Molecular Biology Techniques, Molecular Biology, Biology and life sciences, Endothelial Cells, Epithelial Cells, Cell Biology, Gene regulation, Biological Tissue, HEK293 Cells, Mutation, RNA, Gene expression
Abstract

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells., Author summary Venous thromboembolism (VTE) is a multifactorial disease in which the genetic burden is high. We here present the case of a French family with multiple relatives affected with unprovoked VTE (i.e. that occurred in the absence of clinical risk factors) in which no thrombophilia defects had been identified. Adopting a whole exome sequencing approach, we identified an extremely rare variant located in the Microtubule-associated serine/threonine-protein kinase-2 (MAST2) gene that perfectly segregates with the VTE phenotype and that interferes with hemostatic balance of endothelial cells. Our results pave the way for adding MAST2 to the list of genes to be sequenced and looked for in thrombophilia families with unprovoked VTE.

Published
2021
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2. The beta secretase BACE1 regulates the expression of insulin receptor in the liver

Author

Meakin, Paul J., Mezzapesa, Anna, Benabou, Eva, Haas, Mary E., Bonardo, Bernadette, Grino, Michel, Brunel, Jean-Michel, Desbois-Mouthon, Christèle, Biddinger, Sudha B., Govers, Roland, Ashford, Michael L. J., Peiretti, Franck, Division of Molecular & Clinical Medicine [Dundee, UK], Ninewells Hospital & Medical school [Dundee, UK], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Boston Children's Hospital, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical Research Council (MR/K003291/1) and British Heart Foundation (PG/15/44/31574), Institut National du Cancer (INCa-DGOS_5790), GEFLUC and Ligue Contre le Cancer (Comité de Paris), peiretti, franck, Centre recherche en CardioVasculaire et Nutrition (C2VN), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Glycosylation, Hepatocellular carcinoma, secretase, Science, Médecine humaine et pathologie, Mice, Transgenic, amyloide, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Mice, récepteur de l'insuline, Protein Domains, Antigens, CD, Neoplasms, mental disorders, Diabetes Mellitus, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Aspartic Acid Endopeptidases, Humans, Insulin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, cancer du foie, glucose, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, maladie hépatique, Insulin signalling, Type 2 diabetes, Proteases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Receptor, Insulin, Mice, Inbred C57BL, HEK293 Cells, Liver, lcsh:Q, Female, Human health and pathology, Amyloid Precursor Protein Secretases, ectodomaine, Signal Transduction, homéostasie glucidique, diabète
Abstract

Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management., A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.

Published
2018
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3. A photoswitchable GABA receptor channel blocker

Author

Maleeva, Galyna, Wutz, Daniel, Rustler, Karin, Nin‐Hill, Alba, Rovira, Carme, Petukhova, Elena, Bautista‐Barrufet, Antoni, Gomila‐Juaneda, Alexandre, Scholze, Petra, Peiretti, Franck, Alfonso‐Prieto, Mercedes, König, Burkhard, Gorostiza, Pau, Bregestovski, Piotr, ProdInra, Migration, Aix Marseille Université (AMU), University of Regensburg, University of Barcelona, Institució Catalana de Recerca i Estudis Avançats (ICREA), Kazan State Medical University (KSMU), Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), University of Vienna [Vienna], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Bio and Geosciences Forschungszentrum Jülich, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 2017-SGR-1442,CTQ2016-80066R,BCV-2016-3-0005 BCV-2016-2-0002,2017-SGR-1442,18-15-00313,PCIN-2015-163-C02-01, and Kazan State Medical University

Subjects
Male, Models, Molecular, Mice, Inbred ICR, Light, Brain, CHO Cells, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Receptors, GABA-A, Research Papers, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Cricetulus, Chloride Channels, Animals, Female, ddc:610, GABA-A Receptor Antagonists, Research Paper
Abstract

International audience; Background and Purpose Anion-selective Cys-loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride-selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light-controllable modulator of GABA receptors, we constructed azobenzene-nitrazepam (Azo-NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group. Experimental Approach The experiments were carried out on cultured cells expressing Cys-loop receptors of known subunit composition and in brain slices using patch-clamp. Site-directed mutagenesis and molecular modelling approaches were applied to evaluate the mechanism of action of Azo-NZ1. Key Results At visible light, being in trans-configuration, Azo-NZ1 blocked heteromeric alpha 1/beta 2/gamma 2 GABA(A) receptors, rho 2 GABA(A) (GABA(C)), and alpha 2 glycine receptors, whereas switching the compound into cis-state by UV illumination restored the activity. Azo-NZ1 successfully photomodulated GABAergic currents recorded from dentate gyrus neurons. We demonstrated that in trans-configuration, Azo-NZ1 blocks the Cl-selective ion pore of GABA receptors interacting mainly with the 2 ' level of the TM2 region. Conclusions and Implications Azo-NZ1 is a soluble light-driven Cl-channel blocker, which allows photo-modulation of the activity induced by anion-selective Cys-loop receptors. Azo-NZ1 is able to control GABAergic postsynaptic currents and provides new opportunities to study inhibitory neurotransmission using patterned illumination.

Published
2019
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4. Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

Author

Saultier, Paul, Vidal, Lea, Canault, Matthias, Bernot, Denis, Falaise, Celine, Pouymayou, Catherine, Bordet, Jean-Claude, Saut, Noémie, Rostan, Agathe, Baccini, Véronique, Peiretti, Franck, Favier, Marie, Lucca, Pauline, Deleuze, Jean-François, Olaso, Robert, Boland, Anne, Morange, Pierre-Emmanuel, Gachet, Christian, Malergue, Fabrice, Faure, Sixtine, Eckly, Anita, Tregouet, David-Alexandre, Poggi, Marjorie, Alessi, Marie-Christine, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), APHM, French Reference Ctr Inherited Platelet Disorders, Hôpital de la Timone [CHU - APHM] (TIMONE), Hémostase, Inflammation et sepsis (EA 4609), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], UMR S 1166, Team Genom & Pathophysiol Cardiovasc Dis, UMR S 1166, Université Pierre et Marie Curie (Paris 6), Université Paris-Sorbonne (UP4), Centre National de Génotypage, Institut de Génomique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fédération de Médecine Translationelle de Strasbourg (FMTS), Etablissement Français du Sang, Université de Strasbourg (UNISTRA), UMR S949, Life Sciences Global Assay and Applications Development, Beckman Coulter Genom SA, Fondation pour la Recherche Medicale FDM20150633607, ICAN Institute for Cardiometabolism and Nutrition ANR-10-IAHU-05, Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Recherche Agronomique ( INRA ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), Hémostase, Inflammation et sepsis, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-VetAgro Sup ( VAS ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Sorbonne (Paris 4), Commissariat à l'Energie Atomique et aux Energies Alternatives, Fédération de Médecine Translationelle de Strasbourg ( FMTS ), Université de Strasbourg ( UNISTRA ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche sur les maladies cardiovasculaires et métaboliques, UMR S 1166, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Adult, Blood Platelets, Male, Platelet Aggregation, Transcription, Genetic, cytométrie de flux, Cytoplasmic Granules, Article, Platelet Biology & its Disorders, Young Adult, genetic disease, maladie génétique, Humans, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Nucleus, Proto-Oncogene Protein c-fli-1, Genetic Variation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, pathophysiologie, Middle Aged, Thrombocytopenia, thrombocyte, biomarker, Megakaryocytes, biomarqueur, Hématologie
Abstract

Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c. 1010G>A and c. 1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers' platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers' platelets, presumably due to a biogenesis defect. Additionally, 25-29% of the platelets displayed giant a-granules, while a smaller proportion displayed vacuoles (7-9%) and autophagosome-like structures (0-3%). In vitro study of megakaryocytes derived from circulating CD34(+) cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the FLI1 variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in FLI1 variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of FLI1 variant-associated thrombocytopenia.

Published
2017
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5. Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors

Author

Poggi, Marjorie, Canault, Matthias, Favier, Marie, Turro, Ernest, Saultier, Paul, Ghalloussi, Dorsaf, Baccini, Veronique, Vidal, Lea, Mezzapesa, Anna, Chelghoum, Nadjim, Mohand-Oumoussa, Badreddine, Falaise, Céline, Favier, Rémi, Ouwehand, Willem H, Fiore, Mathieu, Peiretti, Franck, Morange, Pierre-Emmanuel, Saut, Noémie, Bernot, Denis, Greinacher, Andreas, BioResource, Nihr, Nurden, Alan T, Nurden, Paquita, Freson, Kathleen, Trégouët, David-Alexandre, Raslova, Hana, Alessi, Marie-Christine, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Wellcome Trust Sanger Institute [Cambridge], NOVABUILD, parent, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CNR Institute of Electronics, Computer and Telecommunication Engineering [Torino] (CNR | IEIIT), CNR Istituto di elettronica e di ingegneria dell'informazione e delle telecomunicazioni (CNR | IEIIT), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR)-National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-IAHU-05, FDM20150633607, (NIHR) RG65966 (FWO-Vlaanderen, Belgium) G.0B17.13N (BOF KU Leuven, Belgium) OT/14/098, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Matériaux Géomatériaux et Environnement, Université Badji Mokhtar - Annaba [Annaba] (UBMA), Institute of Electronics, Computer and Telecommunication Engineering (IEIIT-CNR), Politecnico di Torino [Torino] (Polito)-Consiglio Nazionale delle Ricerche [Torino] (CNR), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Canault, Matthias, Institute of Electronics, Computer and Telecommunication Engineering [Torino] (IEIIT-CNR), Politecnico di Torino = Polytechnic of Turin (Polito)-Consiglio Nazionale delle Ricerche [Torino] (CNR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de la Méditerranée - Aix-Marseille 2 - Institut National de la Recherche Agronomique (INRA) - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Badji Mokhtar [Annaba], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP], Service de pédiatrie, d'hématologie et d'oncologie [CHU La Timone], Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), IEIIT-CNR, Politecnico di Torino [Torino] (Polito), Université Bordeaux Segalen - Bordeaux 2 - CHU Bordeaux [Bordeaux], University of Leuven, Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], and Apollo - University of Cambridge Repository

Subjects
Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Transcription, Genetic, Antigens, CD34, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], progéniteur érythrocytaire, mégacaryocyte, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Familial thrombocytopenia, cellule hematopoietique, ComputingMilieux_MISCELLANEOUS, séquence d'adn, CDC42, Cell Differentiation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Articles, CR-1 GENE, Pedigree, Phenotype, Female, Life Sciences & Biomedicine, Megakaryocytes, EXPRESSION, Platelets, Blood Platelets, Genotype, DNA-BINDING, Immunology, Médecine humaine et pathologie, gène autosomal, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 1102 Cardiovascular Medicine And Haematology, hematopoietic cell, Thrombopoiesis, Megakaryocyte, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], hémopathie, Humans, Family, Germ-Line Mutation, Science & Technology, Hyperplasia, Proto-Oncogene Proteins c-ets, MUTATIONS, Platelet Count, THROMBOCYTOPENIA, AUTOINHIBITION, Hematopoietic Stem Cells, Hematopoiesis, Blood Cell Count, Repressor Proteins, thrombocyte, Gene Expression Regulation, cellule germinale, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, TEL, TEL/AML1 FUSION PROTEIN, Human health and pathology, germ-line cells, LEUKEMIA
Abstract

Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to co-repressors. We also observed large expansion of CFU-MKs derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton Cdc42 and RhoA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels. ispartof: Haematologica vol:102 issue:2 pages:282-294 ispartof: location:Italy status: published

Published
2017
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6. The Transcriptional Effects of PCB118 and PCB153 on the Liver, Adipose Tissue, Muscle and Colon of Mice: Highlighting of Glut4 and Lipin1 as Main Target Genes for PCB Induced Metabolic Disorders

Author

Mesnier, Aurélia, Champion, Serge, Louis, Laurence, Sauzet, Christophe, May, Phealay, Portugal, Henri, Benbrahim, Karim, Abraldes, Joelle, Alessi, Marie-Christine, Amiot-Carlin, Marie-Josephe, Peiretti, Franck, Piccerelle, Philippe, Nalbone, Gilles, Villard, Pierre-Henri, Institut méditerranéen de biodiversité et d'écologie marine et continentale ( IMBE ), Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Aix Marseille Université ( AMU ) -Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique ( CNRS ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire central, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Villard, Pierre-Henri, This work was supported by the PNRPE (Plan National de Recherche sur les Perturbateurs Endocriniens) from the 'Ministère de l'écologie, du développement durable et de l'énergie', Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UMR237-Aix Marseille Université (AMU)-Avignon Université (AU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blood Glucose, Male, EXPRESSION, Transcription, Genetic, Colon, Phosphatidate Phosphatase, lcsh:Medicine, Real-Time Polymerase Chain Reaction, Mice, Metabolic Diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], POLYCHLORINATED-BIPHENYLS, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Animals, EXPOSURE, Muscle, Skeletal, lcsh:Science, Triglycerides, Oligonucleotide Array Sequence Analysis, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, LIPODYSTROPHY, [ SDV.BID ] Life Sciences [q-bio]/Biodiversity, INSULIN-RESISTANCE, Glucose Transporter Type 4, ADIPOCYTE DIFFERENTIATION, Dose-Response Relationship, Drug, [ SDV ] Life Sciences [q-bio], lcsh:R, DEATH, Nuclear Proteins, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, GAMMA, Polychlorinated Biphenyls, TRANSPORT, Mice, Inbred C57BL, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Adipose Tissue, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, OBESITY, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Q, Research Article
Abstract

International audience; Epidemiological studies have associated environmental exposure to polychlorinated biphe-nyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equi-molar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/ or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregu-lation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved.

Published
2015
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7. CMTX1 patients' cells present genomic instability corrected by CamKII inhibitors

Author

Saleh, Mones, Burkhardt, Gess, Benoit, Bordignon, Alexandre, Altié, Peter, Young, Frederic, Bihel, Marc, Fraterno, Franck, Peiretti, Michel, Fontes, Mones, Saleh, Gess, Burkhardt, Bordignon, Benoit, Altié, Alexandre, Young, Peter, Bihel, Frederic, Fraterno, Marc, Peiretti, Franck, Fontes, Michel, Aix Marseille Université (AMU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), RWTH Aachen University, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and ProdInra, Migration

Subjects
Medicine(all), Adult, Male, Peripheral neuropathies, Adolescent, Research, [SDV]Life Sciences [q-bio], Drug development, Fibroblasts, CMT disorder, Genomic Instability, Cell Line, [SDV] Life Sciences [q-bio], Mice, Young Adult, Charcot-Marie-Tooth Disease, Animals, Humans, Genetics(clinical), Pharmacology (medical), Female, Enzyme Inhibitors, Erratum, Calcium-Calmodulin-Dependent Protein Kinase Type 2
Abstract

International audience; Background: We previously described that fibroblasts from animal models of CMTX1 present genomic instability and poor connexon activity. In vivo, these transgenic mice present motor deficits. This phenotype could be significantly reverted by treatment with (CamKII) inhibitors. The objective of this study is to translate our findings to patients. Methods: We cultured fibroblasts from skin biopsies of CMTX1 patients and analyzed cells for genomic instabilty, connexon activity, and potential correction by CamKII inhibitors. Results: The phenotypic analysis of these cells confirmed strong similarities between the GJB1 transgenic mouse cell lines and CMTX1 patient fibroblast cell lines. Both present mitotic anomalies, centrosome overduplication, and connexon activity deficit. This phenotype is corrected by CamKII inhibitors. Conclusions: Our data demonstrate that fibroblasts from CMTX1 patients present a phenotype similar to transgenic lines that can be corrected by CamKII inhibitors. This presents a track to develop therapeutic strategies for CMTX1 treatment.

Published
2015
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8. Photocontrol of Endogenous Glycine Receptors In Vivo

Author

Elvira Mukhametova, Alba Nin-Hill, Franck Peiretti, Burkhard König, Daniel Wutz, Piotr Bregestovski, Marat A. Mukhamedyarov, Xavier Rovira, Miquel Bosch, Daria Ponomareva, Carme Rovira, Pau Gorostiza, Karin Rustler, Galyna Maleeva, Antoni Bautista-Barrufet, Alexandre M. J. Gomila, Elena Petukhova, Mercedes Alfonso-Prieto, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), Barcelona Institute of Science and Technology (BIST), University of Regensburg, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona (UB), University of Barcelona, Kazan Federal University (KFU), Kazan State University (KPFU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute of Neuroscience and Medicine [Jülich] (INM-1), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Universitat de Barcelona and the Intitut de Recerca en Química Teòrica i Computacional (IQTCUB), Institució Catalana de Recerca i Estudis Avançats (ICREA), ERA SynBIO grant MODULIGHTOR PCIN-2015-163-C02-01Russian Science Foundation (RSF) 18-15-00313AGAUR/Generalitat de Catalunya (CERCA Programme) 2017-SGR-1442Human Brain Project WAVESCALES (SGA2 Grant) 785907MINECO CTQ2016-80066R, and peiretti, franck

Subjects
Male, Clinical Biochemistry, Allosteric regulation, Neurotransmission, Biology, Inhibitory postsynaptic potential, Ligands, 01 natural sciences, Biochemistry, Synaptic Transmission, Mice, [SCCO]Cognitive science, Cricetulus, Receptors, Glycine, In vivo, ddc:570, Drug Discovery, medicine, Animals, photopharmacology, Receptor, Molecular Biology, Glycine receptor, Cells, Cultured, Pharmacology, Neurons, Mice, Inbred ICR, Molecular Structure, 010405 organic chemistry, glycine receptors, [SCCO] Cognitive science, Photochemical Processes, 3. Good health, 0104 chemical sciences, optopharmacology, Molecular Docking Simulation, inhibitory neurotransmission, in vivo, Mechanism of action, Excitatory postsynaptic potential, Molecular Medicine, Female, photoswitch, medicine.symptom, CNS, Neuroscience, Azo Compounds
Abstract

International audience; Glycine receptors (GlyRs) are indispensable for maintaining excitatory/inhibitory balance in neuronal circuits that control reflexes and rhythmic motor behaviors. Here we have developed Glyght, a GlyR ligand controlled with light. It is selective over other Cys-loop receptors, is active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understanding inhibitory circuits in intact animals and to developing drug-based phototherapies.

Published
2020
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