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1. Multiparametric characterization of red blood cell physiology after hypotonic dialysis based drug encapsulation process

Author

Angelo D'Alessandro, Travis Nemkov, Virginie Salnot, Alexander Scheer, Philippe Connes, Philippe Joly, Florian Dupuy, Bastien Laperrousaz, Catherine Lavazec, Emilie-Fleur Gautier, Elie Nader, Diana Piedrahita, Agnès Cibiel, Patrick Mayeux, Mélanie Robert, ERYTECH Pharma, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Colorado Anschutz [Aurora], Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, and Lavazec, Catherine

Subjects
Drug, Morphology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Drug carrier, media_common.quotation_subject, Physiology, Omics, Red blood cells, Pharmacokinetics, In vivo, hemic and lymphatic diseases, medicine, General Pharmacology, Toxicology and Pharmaceutics, media_common, Senescence markers, Chemistry, hemic and immune systems, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Red blood cell, l-Asparaginase, medicine.anatomical_structure, Tonicity, Hypotonic dialysis, Dialysis (biochemistry), Rheology, Intracellular, circulatory and respiratory physiology
Abstract

International audience; Red blood cells (RBCs) can act as carriers for therapeutic agents and can substantially improve the safety, pharmacokinetics, and pharmacodynamics of many drugs. Maintaining RBCs integrity and lifespan is important for the efficacy of RBCs as drug carrier. We investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and integrity. Several parameters were compared between processed RBCs loaded with l-asparaginase (“eryaspase”), processed RBCs without drug and non-processed RBCs. Processed RBCs were less hydrated and displayed a reduction of intracellular content. We observed a change in the metabolomic but not in the proteomic profile of processed RBCs. Encapsulation process caused moderate morphological changes and was accompanied by an increase of RBCs-derived Extracellular Vesicles release. Despite a decrease in deformability, processed RBCs were not mechanically retained in a spleen-mimicking device and had increased surface-to-volume ratio and osmotic resistance. Processed RBCs half-life was not significantly affected in a mouse model and our previous phase 1 clinical study showed that encapsulation of asparaginase in RBCs prolonged its in vivo half-life compared to free forms. Our study demonstrated that encapsulation by hypotonic dialysis may affect certain characteristics of RBCs but does not significantly affect the in vivo longevity of RBCs or their drug carrier function.

Published
2022

2. Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction

Author

Chevalier, Philippe, Moreau, Adrien, Bessière, Francis, Richard, Sylvain, Chahine, Mohamed, Millat, Gilles, Morel, Elodie, Paganelli, Franck, Lesavre, Nathalie, Placide, Leslie, Montestruc, François, Ankou, Bénédicte, Puertas, Rosa Doñate, Asatryan, Babken, Delinière, Antoine, MORNET, Dominique, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Hôpital Louis Pradel [CHU - HCL], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche de l’Institut universitaire en santé mentale de Québec [Canada] (CERVO), Département de réadaptation (Faculté de médecine de l'Université Laval) [Canada], Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Faculté de médecine de l'Université Laval [Québec] (ULaval), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Hôpital Nord [CHU - APHM], eXYSTAT [Malakoff], Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and Bern University Hospital [Berne] (Inselspital)

Subjects
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Acute ventricular fibrillation, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, ST-elevation myocardial infarction (STEMI), [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, GJA1 variants, Sudden cardiac death, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Physiology (medical), Connexin 43, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Cardiology and Cardiovascular Medicine, 610 Medizin und Gesundheit
Abstract

Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300

Published
2022
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3. The PPARγ pathway determines electrophysiological remodelling and arrhythmia risks in DSC2 arrhythmogenic cardiomyopathy

Author

Jean‐Baptiste Reisqs, Adrien Moreau, Azzouz Charrabi, Yvonne Sleiman, Albano C. Meli, Gilles Millat, Veronique Briand, Philippe Beauverger, Sylvain Richard, Philippe Chevalier, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sanofi Aventis R&D [Chilly-Mazarin], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hospices Civils de Lyon (HCL), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, and MORNET, Dominique

Subjects
[SDV] Life Sciences [q-bio], Desmocollins, PPAR gamma, [SDV]Life Sciences [q-bio], Molecular Medicine, Medicine (miscellaneous), Humans, Arrhythmias, Cardiac, Cardiac Electrophysiology, ComputingMilieux_MISCELLANEOUS, Arrhythmogenic Right Ventricular Dysplasia
Abstract

International audience; No abstract available

Published
2021

4. A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing

Author

Céline Bouchet-Séraphin, John Rendu, Cécile Acquaviva-Bourdain, Mathieu Cerino, Aurélien Perrin, Frédérique Audic, Jon Andoni Urtizberea, Julien Fauré, Roseline Froissart, Mireille Cossée, Martin Krahn, Corinne Metay, Laurence Michel-Calemard, Damien Sternberg, Judith Melki, Jean Pouget, Emmanuelle Campana-Salort, Nathalie Seta, Annamaria Molon, Juliette Nectoux, François Petit, Valérie Biancalana, Brigitte Chabrol, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], 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), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de biologie et pathologie Est, Hospices Civils de Lyon (HCL), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal [CHU Lyon] (Centre de Biologie et Pathologie Est), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est, Hôpital de la Timone [CHU - APHM] (TIMONE), Filière Neuromusculaire (FILNEMUS), Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des maladies neuromusculaires et de la SLA, Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biochimie Métabolique et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Pitié-Salpêtrière [AP-HP], Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112))

Subjects
Consensus, [SDV]Life Sciences [q-bio], MEDLINE, Computational biology, Biology, DNA sequencing, Article, 03 medical and health sciences, Gene panel, Genetics, Humans, Genetic Testing, Gene, Genetics (clinical), Societies, Medical, 0303 health sciences, Genetic heterogeneity, 030305 genetics & heredity, Neuromuscular Diseases, Sequence Analysis, DNA, Diagnostic strategy, 3. Good health, Practice Guidelines as Topic, France, Genetic diagnosis, Core gene
Abstract

International audience; Next-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies. The strategy is based on the determination of 13 clinical and/or histological entry-diagnosis groups, and consists for each group either in a successive NGS analysis of a "core gene list" followed in case of a negative result by the analysis of an "exhaustive gene list", or in the NGS analysis of a "unique exhaustive gene list".

Published
2019

5. Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1

Author

Juliette Berger, Marie Vigan, Bruno Pereira, Thu Thuy Nguyen, Roseline Froissart, Nadia Belmatoug, Florence Dalbiès, Agathe Masseau, Christian Rose, Christine Serratrice, Yves-Marie Pers, Ivan Bertchansky, Fabrice Camou, Monia Bengherbia, Céline Bourgne, Catherine Caillaud, Magali Pettazzoni, Amina Berrahal, Jérôme Stirnemann, France Mentré, Marc G. Berger, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), service de Biostatistiques, DRCI, Centre Hospitalier Universitaire de Clermont-Ferrand, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Hôpitaux Universitaires Paris Nord Val de Seine, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Médecine Interne [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital St-André, Réanimation, CHU Bordeaux [Bordeaux], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Service de biochimie métabolique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Universitaire de Genève, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), CHU Clermont-Ferrand, Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Claude Huriez [Lille], CHU Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Oncology, Male, [SDV]Life Sciences [q-bio], Disease, Glucosylceramidase/metabolism/pharmacokinetics/therapeutic use, Monocytes, 0302 clinical medicine, Monocytes/metabolism, Medicine, Pharmacology (medical), Precision Medicine, Child, ComputingMilieux_MISCELLANEOUS, ddc:616, Aged, 80 and over, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Enzyme replacement therapy, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Glucosylceramidase, Female, medicine.drug, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Imiglucerase, Adolescent, Models, Biological, Gaucher Disease/drug therapy/metabolism, 03 medical and health sciences, Young Adult, Pharmacotherapy, Pharmacokinetics, Internal medicine, Humans, Enzyme Replacement Therapy, Aged, Pharmacology, Gaucher Disease, business.industry, nutritional and metabolic diseases, Confidence interval, 030104 developmental biology, ddc:618.97, business, Glucocerebrosidase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase. A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8–1; p

Published
2019

6. A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)

Author

Nathalie Bonello-Palot, Chiara Pisciotta, Mario Sabatelli, Rita Horvath, Stefano C. Previtali, Alessandro Geroldi, Esra Battaloglu, Julian Blake, André Mégarbané, Raquel Guimarães-Costa, Matilde Laura, Alberto A. Zambon, Angelo Schenone, Lucio Santoro, Sabrina Sacconi, Philippe Latour, Yesim Parman, Michael E. Shy, Chiara Gemelli, Irene Tramacere, Sarah Leonard-Louis, Mounia Bellatache, Nicolas Lévy, Steven S. Scherer, Byung Ok Choi, Aldo Quattrone, S. Attarian, Tatsufumi Murakami, Lois Dankwa, Paola Valentino, David N. Herrmann, Marco Luigetti, Mary M. Reilly, Stefania Magri, Fiore Manganelli, Davide Pareyson, Meriem Tazir, Chelsea Bacon, Guilhem Solé, Alessandra Bolino, Tanya Stojkovic, Giulia Ricci, Pareyson, D., Stojkovic, T., Reilly, M. M., Leonard-Louis, S., Laura, M., Blake, J., Parman, Y., Battaloglu, E., Tazir, M., Bellatache, M., Bonello-Palot, N., Levy, N., Sacconi, S., Guimaraes-Costa, R., Attarian, S., Latour, P., Sole, G., Megarbane, A., Horvath, R., Ricci, G., Choi, B. -O., Schenone, A., Gemelli, C., Geroldi, A., Sabatelli, M., Luigetti, M., Santoro, L., Manganelli, F., Quattrone, A., Valentino, P., Murakami, T., Scherer, S. S., Dankwa, L., Shy, M. E., Bacon, C. J., Herrmann, D. N., Zambon, A., Tramacere, I., Pisciotta, C., Magri, S., Previtali, S. C., Bolino, A., CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Service de Neurologie, CHU Mustapha, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département de génétique médicale [Hôpital de la Timone - APHM], 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), CHU Nice, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Filière Neuromusculaire (FILNEMUS), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jérôme Lejeune, CHU Trousseau [APHP], University of Pisa - Università di Pisa, Department of Neuroscience, Ophtalmology and Genetics, Genova, Università cattolica del Sacro Cuore [Roma] (Unicatt), Department of Neuroscience, Catholic University, Roma, University of Naples Federico II, Institute of Bioimaging and Molecular Physiology [Germaneto], National Research Council [Italy] (CNR), Istituto di Ricerche Farmacologiche 'Mario Negri', 20156 Milan, Human Inherited Neuropathies Unit, San Raffaele Scientific Institute-INSPE-Institute for Experimental Neurology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Bonello-Palot, Nathalie [0000-0002-8657-1271], Previtali, Stefano C [0000-0003-2546-4357], Bolino, Alessandra [0000-0002-8980-4878], Apollo - University of Cambridge Repository, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), and University of Naples Federico II = Università degli studi di Napoli Federico II

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Cord, Adolescent, Myotubularin, Glaucoma, Disease, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Charcot-Marie-Tooth Disease, Internal medicine, medicine, Humans, Young adult, Child, Loss function, Retrospective Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, hereditary neuropathies, Retrospective cohort study, Middle Aged, Protein Tyrosine Phosphatases, Non-Receptor, medicine.disease, Phenotype, 3. Good health, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, Neurology, Child, Preschool, Mutation, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; Objective Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. Methods We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. Results There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. Interpretation This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019

Published
2019

7. Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics

Author

Stéphane Marret, Monique Piraud, Carine Pilon, Tony Pereira, Soumeya Bekri, Abdellah Tebani, Lenaig Abily-Donval, Farid Zerimech, Isabelle Schmitz-Afonso, Jérôme Ausseil, Carlos Afonso, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, CHU Amiens-Picardie, Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, CHU Lille, Institut Pasteur de Lille, Université de Lille, Université de Rouen Normandie [UNIROUEN], Chimie Organique et Bioorganique : Réactivité et Analyse [COBRA], Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] [Centre de Biologie et de Pathologie], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, and Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen]

Subjects
Arylsulfatase B, Male, [SDV]Life Sciences [q-bio], Mucopolysaccharidosis type VI, Tandem mass spectrometry, lcsh:Chemistry, 0302 clinical medicine, Lysosomal storage disease, Biomarker discovery, skin and connective tissue diseases, Child, lcsh:QH301-705.5, Spectroscopy, mucopolysaccharidosis type VI, mass spectrometry, 0303 health sciences, Mucopolysaccharidosis VI, Chemistry, General Medicine, Middle Aged, metabolomics, Computer Science Applications, Phenotype, Child, Preschool, Metabolome, Female, Metabolic Networks and Pathways, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, In silico, Computational biology, Catalysis, Article, inherited metabolic diseases, Inorganic Chemistry, 03 medical and health sciences, Young Adult, Metabolomics, medicine, Humans, Physical and Theoretical Chemistry, lysosomal storage diseases, Molecular Biology, 030304 developmental biology, Aged, Maroteaux-Lamy syndrome, Maroteaux–Lamy syndrome, Organic Chemistry, nutritional and metabolic diseases, Computational Biology, Molecular Sequence Annotation, medicine.disease, lcsh:Biology (General), lcsh:QD1-999, 030217 neurology & neurosurgery
Abstract

Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux&ndash, Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition.

Published
2018

8. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Author

Pierre Kieffer, Jean-Philippe Girardet, Khaldia Belabbas, Anne Lienhardt, Ahlam Azar-Kolakez, François Labarthe, Anne-Marie Colin Gorsky, Olivier Lascols, Béatrice Dubern, Franck Boccara, Catherine Tamarindi, Mathilde Di Filippo, Jean-Claude Carel, Félicien MBou, Alice Horovitz, René Wintjens, Dominique Bozon, Mathilde Jolly, Fabienne Dufernez, Ariel Cohen, François Feillet, Patrick Tounian, A. Karsenty, Université Libre de Bruxelles [Bruxelles] (ULB), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Laboratoire Commun de Biologie et Génétiques Moléculaires (LCBGM [Hôpital Saint-Antoine]), AP-HP - Hôpital Saint-Antoine, Service d’Endocrinologie [Hôpital le Lamentin Bourg - CHU de la Martinique], CHU de la Martinique [Fort de France]-Hôpital Le Lamentin Bourg [CHU de la Martinique], CHU de la Martinique [Fort de France], Service de Gastroentérologie et Nutrition Pédiatrique [APHP Trousseau], CHU Trousseau [APHP], Service d'Endocrinologie, Diabétologie et Nutrition [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Service d'endocrinologie diabétologie pédiatrique [CHU Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine pédiatrique [CHRU Tours-Clocheville], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier d'Argenteuil, Service de Cardiologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de Maternité [CHU Hagueneau], Centre Hospitalier Hagueneau (CH Hagueneau), Service de Médecine Interne [CH Mulhouse- E. Muller], Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université libre de Bruxelles (ULB), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Victor Dupouy, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biology-Imaging District of East-Hospitals Group of AP-HP (Assistance Publique-Hopitaux de Paris), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, Models, Molecular, Protein Conformation, alpha-Helical, 0301 basic medicine, Apolipoprotein E, Genotyping Techniques, Apolipoprotein B, Familial hypercholesterolemia, apolipoprotéine, 030204 cardiovascular system & hematology, medicine.disease_cause, Biochemistry, Cohort Studies, Exon, 0302 clinical medicine, Endocrinology, Child, apolipoprotein E, Genetics, Mutation, familial hypercholesterolemia, biology, cholestérol, Exons, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endocrinologie, 3. Good health, phénotype, Phenotype, Kexin, Female, lipids (amino acids, peptides, and proteins), France, Proprotein Convertase 9, génotype, corrélation, Adult, Biochimie, hypercholestérolemie, QD415-436, Hyperlipoproteinemia Type II, Young Adult, 03 medical and health sciences, Apolipoproteins E, apolipoproteins, cholesterol, low density lipoprotein, phenotype/genotype correlation, medicine, Humans, Apolipoproteins B, PCSK9, Cell Biology, medicine.disease, 030104 developmental biology, Receptors, LDL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, LDL receptor, biology.protein, Biologie cellulaire, Patient-Oriented and Epidemiological Research
Abstract

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB, and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identifi ed 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be signifi-cantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

9. Urinary metabolic phenotyping of mucopolysaccharidosis type I combining untargeted and targeted strategies with data modeling

Author

Farid Zerimech, Anaïs Brassier, Bruno J. Gonzalez, Stéphane Marret, Jérôme Ausseil, Carlos Afonso, Abdellah Tebani, Lenaig Abily-Donval, Frédéric M. Vaz, Bénédicte Héron, Soumeya Bekri, Monique Piraud, Pascale de Lonlay, Isabelle Schmitz-Afonso, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, CHU Amiens-Picardie, Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA Necker), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratory Genetic Metabolic Disease, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Amsterdam [Amsterdam] (UvA)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Proline, Mucopolysaccharidosis I, In silico, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Dermatan Sulfate, Arginine, Tandem mass spectrometry, Biochemistry, Mass Spectrometry, Dermatan sulfate, 03 medical and health sciences, chemistry.chemical_compound, Mucopolysaccharidosis type I, Metabolomics, Metabolome, Humans, Amino Acids, Child, Chromatography, High Pressure Liquid, Aged, chemistry.chemical_classification, Biochemistry (medical), Infant, General Medicine, Middle Aged, Glutathione, Amino acid, Phenotype, 030104 developmental biology, chemistry, Keratan Sulfate, Case-Control Studies, Child, Preschool, Multivariate Analysis, Female, Heparitin Sulfate, Algorithms
Abstract

International audience; Background =Application of metabolic phenotyping could expand the pathophysiological knowledge of mucopolysaccharidoses (MPS) and may reveal the comprehensive metabolic impairments in MPS. However, few studies applied this approach to MPS.Methods =We applied targeted and untargeted metabolic profiling in urine samples obtained from a French cohort comprising 19 MPS I and 15 MPS I treated patients along with 66 controls. For that purpose, we used ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry following a protocol designed for large-scale metabolomics studies regarding robustness and reproducibility. Furthermore, 24 amino acids have been quantified using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Keratan sulfate, Heparan sulfate and Dermatan sulfate concentrations have also been measured using an LC-MS/MS method. Univariate and multivariate data analyses have been used to select discriminant metabolites. The mummichog algorithm has been used for pathway analysis.Results =The studied groups yielded distinct biochemical phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the groups. Specifically, metabolites related to the amino acid metabolism. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS. Comparison of targeted and untargeted metabolomics data with in silico results yielded arginine, proline and glutathione metabolisms being the most affected.Conclusion =This study is one of the first metabolic phenotyping studies of MPS I. The findings might help to generate new hypotheses about MPS pathophysiology and to develop further targeted studies of a smaller number of potentially key metabolites.

Published
2017

10. LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease

Author

Magali Pettazzoni, Alain Fouilhoux, Philippe Latour, Séverine Ruet, Christine Vianey-Saban, Roseline Froissart, David Cheillan, Thierry Levade, Cécile Pagan, Nathalie Guffon, Marie T. Vanier, Monique Piraud, Dominique P. Germain, Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Métabolomique et maladies métaboliques, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Mérieux, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
0301 basic medicine, Male, Pathology, Embryology, Amniotic fluid, Physiology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gangliosidosis, Biochemistry, Tandem Mass Spectrometry, Prenatal Diagnosis, Medicine and Health Sciences, lcsh:Science, Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Niemann-Pick Disease, Type C, Inherited Metabolic Disorders, 3. Good health, Body Fluids, Gaucher's disease, Blood, Genetic Diseases, Female, Anatomy, Cellular Structures and Organelles, Niemann–Pick disease, Research Article, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Sensitivity and Specificity, Blood Plasma, 03 medical and health sciences, Autosomal Recessive Diseases, Diagnostic Medicine, Hydrops fetalis, Sphingolipidoses, medicine, Humans, Clinical Genetics, Sphingolipids, Fetuses, business.industry, Inborn Errors of Metabolism, lcsh:R, Infant, Newborn, nutritional and metabolic diseases, Biology and Life Sciences, Cell Biology, medicine.disease, Amniotic Fluid, Sphingolipid, Fabry disease, 030104 developmental biology, Metabolic Disorders, Fabry Disease, lcsh:Q, business, Lysosomes, Biomarkers, Gaucher's Disease, Developmental Biology
Abstract

Background The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma. Methodology We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis. Findings The diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively. In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples. Interpretation This multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes.

Published
2017

11. Disseminated actinomycosis treated with clindamycin

Author

Bouttefroy, S., Faure Conter, C., Tristan, A., VALOUR, Florent, Perpoint, T., Reix, P., Thiesse, P., Dijoud, F., Catho, G., Service de Pneumologie Pédiatrique [Hôpital Femme Mère Enfant - CHU de Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-lyon, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Delayed Diagnosis, Biopsy, Clindamycin, Magnetic Resonance Imaging, Long-Term Care, Actinomycosis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Diagnosis, Differential, Pulmonary Alveoli, Diagnosis, Differential, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Child
Abstract

International audience; Actinomycosis is a rare bacterial disease caused by Actinomyces spp., an anaerobic bacteria from the oropharynx, digestive, and female genital tracts. Initial clinical presentation often mimics malignancy, which can lead to a delay in diagnosis. Cervico-facial, genitourinary, digestive, and respiratory features are the most frequent. Few cases are reported in children and risk factors are not well known in this population. We report on the case of an 8-year-old boy with disseminated actinomycosis with cervico-facial, pulmonary, and bone involvement caused by Actinomyces israelii. The infiltrative appearance initially suggested malignancy and the patient was started on chemotherapy for presumed histiocytosis. Evaluation of subsequent tissue samples demonstrated the presence of filamentous structures consistent with fungal or filamentous bacterial infection. Prolonged culture yielded the correct diagnosis. The patient had a severe allergic reaction to piperacillin/tazobactam and was therefore transitioned to clindamycin to complete a 9-month course. This treatment, which has not been reported in children, led to a favorable clinical, biological, and radiological response, with a good clinical tolerance.

Published
2017

12. Vaginal Neoplasia Induced by an Unusual Papillomavirus Subtype in a Woman with Inherited Chromosomally Integrated Human Herpesvirus Type 6A

Author

Pascal Gaucherand, Agnès Gautheret-Dejean, Tarik Gheit, Annie Buenerd, Alexandre Gaymard, Massimo Tommasino, Yahia Mekki, Gautier Chene, Bruno Lina, K Lebail-Carval, Etienne Beaufils, Gery Lamblin, Emilie Frobert, Pascale Bonnafous, Maxime Pichon, PICHON, Maxime, Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Nord des HCL [Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), CHU Charles Foix [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)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Vaginal Neoplasms, Gammapapillomavirus, Herpesvirus 6, Human, Virus Integration, 030106 microbiology, Roseolovirus Infections, Uterine Cervical Neoplasms, Vaginal neoplasm, Biology, Cervical intraepithelial neoplasia, Antibodies, Viral, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Human papillomaviruses, medicine, Humans, Sex organ, Low-grade SIL, Papillomaviridae, Colposcopy, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, High-grade SIL, Vaginal intra-epithelial neoplasia, medicine.diagnostic_test, Inherited chromosomally integrated HHV-6A, Papillomavirus Infections, HPV infection, virus diseases, Obstetrics and Gynecology, Middle Aged, medicine.disease, biology.organism_classification, Uterine Cervical Dysplasia, Squamous intraepithelial lesion, medicine.anatomical_structure, Reproductive Medicine, DNA, Viral, Vagina, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Squamous Intraepithelial Lesions of the Cervix, Genital cancer
Abstract

International audience; We describe here a case of high-grade vaginal squamous lesion in a 54-year-old woman with a papillomaviruses (HPV) genital infection that developed from a cervical low-grade squamous intraepithelial lesion (SIL) to a high-grade SIL (HSIL) on cytological examination.A colposcopy exam led to the detection of suspect vaginal lesions with granulomatous infiltrations, which were classified as a Vaginal Intra-Epithelial Neoplasia grade 2 after pathologists’ analyses. After a laser vaginal surgery and a loop excision of the transformation zone, the analyses of the anatomical pieces using a nearcomplete HPV screening panel revealed an HPV-4 infection that was not detected before in cervical smears. This HPVinfection is associated with a high human herpesvirus type 6A (HHV-6A) viral load in the same anatomical piece. The presence of an inherited chromosomally integrated HHV-6A (iciHHV-6A) was proved in this patient by real-time polymerase chain reaction on hair follicles and nail. This case suggests reconsidering both thebenign nature of low-grade lesions in the female genital tract and the well-known “good” prognosis of low-risk HPV infection, especially when iciHHV-6A is diagnosed. This clinical course insists on the benefits of the multiplex panel use or global sequencing in order to optimize biological testing sensitivity, and so enhance clinical management of infection-induced neoplasia

Published
2017

13. Micriamoeba tesseris nov. gen. nov. sp.: a new taxon of free-living small-sized Amoebae non-permissive to virulent Legionellae

Author

Sophie Jarraud, Patricia Doublet, Bénédicte Coupat-Goutaland, Maud Souchon, Arnaud Risler, Danièle Atlan, M. Reyrolle, Michel Pélandakis, Jérôme Briolay, Microbiologie, adaptation et pathogénie (MAP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Immunité infection vaccination (I2V), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR128-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
MESH: Sequence Analysis, DNA, [SDV]Life Sciences [q-bio], Legionella pneumophila, Environmental Microbiology, Cluster Analysis, Amoeba, MESH: Phylogeny, Phylogeny, 0303 health sciences, education.field_of_study, MESH: DNA, Ribosomal, Phylogenetic tree, biology, MESH: Amoeba, MESH: Escherichia coli, MESH: Environmental Microbiology, 6. Clean water, MESH: Feeding Behavior, MESH: RNA, Protozoan, RNA, Protozoan, food.ingredient, Legionella, Population, Molecular Sequence Data, MESH: DNA, Protozoan, Microbiology, DNA, Ribosomal, Amoebozoa, Amoeba (genus), 03 medical and health sciences, food, Phylogenetics, parasitic diseases, MESH: Genes, rRNA, Escherichia coli, RNA, Ribosomal, 18S, education, 030304 developmental biology, MESH: Molecular Sequence Data, 030306 microbiology, Genes, rRNA, Feeding Behavior, Sequence Analysis, DNA, DNA, Protozoan, biology.organism_classification, MESH: Cluster Analysis, MESH: Legionella pneumophila, respiratory tract diseases, Taxon, MESH: RNA, Ribosomal, 18S
Abstract

International audience; Investigation of soil amoebae in 11 cooling towers allowed us to isolate a major unknown small-sized amoeba population (SZA). However, SZA did not appear to be specific to cooling tower ecosystems since they are also a major amoeba population found in muds isolated from different points of a water treatment plant. The SSU-rDNA sequences from SZA strains did not match any known database sequences, suggesting that SZA constitutes a new amoeba taxon. We isolated and further described one of the SZA that we named Micriamoeba tesseris. The phylogenetic analyses showed that Micriamoeba tesseris belongs to the Amebozoa and branched together with genus Echinamoeba+Vermamoeba vermiformis. Phylogenetic analyses within the Micriamoeba group distinguished different subgroups of Micriamoeba strains according to their origin, i.e. cooling tower or mud. Although Micriamoeba are able to feed on viable E. coli cells, they do not uptake virulent Legionella pneumophila strains, thus enabling them to avoid infection by Legionella. Consequently, Micriamoeba is not directly involved in L. pneumophila multiplication. However, an indirect role of Micriamoeba in Legionella risk is discussed.

Published
2012

14. Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells

Author

Diana Toli, Elise Roy, Thomas Lemonnier, Isabelle Rouvet, Delphine Bohl, Stéphane Blanchard, Stéphanie Bigou, Jean Michel Heard, Sandrine Vitry, Roseline Froissart, Rétrovirus et Transfert Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Laboratoire des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon (HCL)-CHU de Lyon-GH Est-Centre de Biologie et de Pathologie Est - CBPE, Centre de Biotechnologie cellulaire, Hospices Civils de Lyon (HCL), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Biologie et de Pathologie Est - CBPE, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Acetylglucosaminidase, [SDV]Life Sciences [q-bio], MESH: Neurons, Fibroblast growth factor, Mucopolysaccharidosis III, 0302 clinical medicine, MESH: Child, Lysosomal storage disease, Induced pluripotent stem cell, Child, MESH: Mucopolysaccharidosis III, Genetics (clinical), Cells, Cultured, Neurons, 0303 health sciences, Cell Differentiation, General Medicine, Neural stem cell, Cell biology, medicine.anatomical_structure, Child, Preschool, symbols, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stem cell, MESH: Cells, Cultured, MESH: Cell Differentiation, MESH: Mutation, Induced Pluripotent Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Induced Pluripotent Stem Cells, Models, Biological, 03 medical and health sciences, symbols.namesake, Lysosome, Neurosphere, MESH: Cell Proliferation, Acetylglucosaminidase, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, Cell Proliferation, MESH: Humans, MESH: Child, Preschool, MESH: Models, Biological, Golgi apparatus, Fibroblasts, medicine.disease, MESH: Male, MESH: Fibroblasts, Mutation, MESH: Heparan Sulfate Proteoglycans, Lysosomes, MESH: Female, 030217 neurology & neurosurgery, Heparan Sulfate Proteoglycans, MESH: Lysosomes
Abstract

International audience; By providing access to affected neurons, human induced pluripotent stem cells (iPSc) offer a unique opportunity to model human neurodegenerative diseases. We generated human iPSc from the skin fibroblasts of children with mucopolysaccharidosis type IIIB. In this fatal lysosomal storage disease, defective α-N-acetylglucosaminidase interrupts the degradation of heparan sulfate (HS) proteoglycans and induces cell disorders predominating in the central nervous system, causing relentless progression toward severe mental retardation. Partially digested proteoglycans, which affect fibroblast growth factor signaling, accumulated in patient cells. They impaired isolation of emerging iPSc unless exogenous supply of the missing enzyme cleared storage and restored cell proliferation. After several passages, patient iPSc starved of an exogenous enzyme continued to proliferate in the presence of fibroblast growth factor despite HS accumulation. Survival and neural differentiation of patient iPSc were comparable with unaffected controls. Whereas cell pathology was modest in floating neurosphere cultures, undifferentiated patient iPSc and their neuronal progeny expressed cell disorders consisting of storage vesicles and severe disorganization of Golgi ribbons associated with modified expression of the Golgi matrix protein GM130. Gene expression profiling in neural stem cells pointed to alterations of extracellular matrix constituents and cell-matrix interactions, whereas genes associated with lysosome or Golgi apparatus functions were downregulated. Taken together, these results suggest defective responses of patient undifferentiated stem cells and neurons to environmental cues, which possibly affect Golgi organization, cell migration and neuritogenesis. This could have potential consequences on post-natal neurological development, once HS proteoglycan accumulation becomes prominent in the affected child brain.

Published
2011

15. Molecular diversity and high virulence of Legionella pneumophila strains isolated from biofilms developed within a warm spring of a thermal spa

Author

Danièle Atlan, Zineddine Chaabna, Françoise Forey, Christophe Gilbert, Dominique Fontvieille, Sophie Jarraud, M. Reyrolle, Centre Alpin de Recherche sur les Réseaux Trophiques et Ecosystèmes Limniques (CARRTEL), Institut National de la Recherche Agronomique (INRA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie, adaptation et pathogénie (MAP), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), This study is supported by grants from the Centre National de la Recherche Scientifique and the Université Lyon 1., BMC, Ed., Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR128-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA, Bacterial, Microbiology (medical), Bacterial Toxins, lcsh:QR1-502, Virulence, Microbiology, Legionella pneumophila, lcsh:Microbiology, Hot Springs, 03 medical and health sciences, Molecular typing, Spring (hydrology), Humans, Biofilms, Warm spring, Biodiversity, LEGIONNAIRES-DISEASE, ACANTHAMOEBA-CASTELLANII, CATALASE-PEROXIDASES, INTRACELLULAR GROWTH, HUMAN PATHOGEN, FRESH-WATER, GENE, IDENTIFICATION, SEROGROUPS, SEQUENCE, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, Acanthamoeba castellanii, 0303 health sciences, geography, Microbial toxins, geography.geographical_feature_category, biology, 030306 microbiology, Biofilm, Genetic Variation, Contamination, biology.organism_classification, Electrophoresis, Gel, Pulsed-Field, Molecular Typing, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Parasitology, France, Research Article
Abstract

Background Several cases of legionellosis have been diagnosed in the same French thermal spa in 1986, 1994 and 1997. L. pneumophila serogroup 1 (Lp1) strains have been isolated from several patients, but the source of contamination was not identified despite the presence of different Lp1 in water samples of the three natural springs feeding the spa at this period. Results Our strategy was to investigate L. pneumophila (Lp) strains from natural biofilms developed in a sulphur-rich warm spring of this contaminated site. Biofilm analysis revealed the presence of three Lp serogroups (Lp1, Lp10 and Lp12). Surprisingly, Lp10 and Lp12 were not reported in the previous described studies from water samples. Besides, the new seven Lp1 we isolated exhibit a high molecular diversity and have been differentiated in five classes according to their DNA genome patterns obtained by PFGE and mip sequences. It must be noted that these DNA patterns are original and unknown in databases. Interestingly, the 27 Lp environmental strains we isolated display a higher cytotoxicity and virulence towards the amoeba Acanthamoeba castellanii than those of known Lp1 epidemic strains. Conclusion The characteristics of Legionella pneumophila Lp1 strains isolated from the warm spring are in agreement with their presence in biofilms and their probable long-term persistence in this ecosystem.

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16. Defining the landscape of TIA1 and SQSTM1 digenic myopathy.

Author

Panos-Basterra P, Theuriet J, Nadaj-Pakleza A, Magot A, Lannes B, Marcorelles P, Behin A, Masingue M, Caillon F, Malek Y, Fenouil T, Bas J, Menassa R, Michel-Calemard L, Streichenberger N, Simon JP, Bouhour F, Evangelista T, Métay C, Pegat A, Stojkovic T, and Fernández-Eulate G

Subjects
Humans, Male, Middle Aged, Adult, Muscle, Skeletal pathology, Aged, Female, Mutation, Phenotype, Sequestosome-1 Protein genetics, T-Cell Intracellular Antigen-1 genetics, Distal Myopathies genetics, Distal Myopathies pathology
Abstract

TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Published
2024
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17. Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.

Author

Caruso M, Mazzatenta D, Asioli S, Costanza G, Trivellin G, Franke M, Abboud D, Hanson J, Raverot V, Pétrossians P, Beckers A, Cappa M, and Daly AF

Subjects
Adult, Humans, Child, Female, Child, Preschool, Growth Hormone metabolism, Gigantism genetics, Gigantism therapy, Gigantism metabolism, Acromegaly pathology, Human Growth Hormone, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked therapy, Pituitary Neoplasms complications, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology
Abstract

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101 , a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs., Competing Interests: AD, GT, and AB hold a patent on GPR101 and its function US Patent No. 10,350,273, Treatment of Hormonal Disorders of Growth. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Caruso, Mazzatenta, Asioli, Costanza, Trivellin, Franke, Abboud, Hanson, Raverot, Pétrossians, Beckers, Cappa and Daly.)

Published
2024
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18. Spatial Transcriptomics Reveals Signatures of Histopathological Changes in Muscular Sarcoidosis.

Author

Lequain H, Dégletagne C, Streichenberger N, Valantin J, Simonet T, Schaeffer L, Sève P, and Leblanc P

Subjects
Humans, Granuloma, Cytokines metabolism, Muscle, Skeletal metabolism, Gene Expression Profiling, Sarcoidosis genetics, Sarcoidosis pathology
Abstract

Sarcoidosis is a multisystemic disease characterized by non-caseating granuloma infiltrating various organs. The form with symptomatic muscular involvement is called muscular sarcoidosis. The impact of immune cells composing the granuloma on the skeletal muscle is misunderstood. Here, we investigated the granuloma-skeletal muscle interactions through spatial transcriptomics on two patients affected by muscular sarcoidosis. Five major transcriptomic clusters corresponding to perigranuloma, granuloma, and three successive muscle tissue areas (proximal, intermediate, and distal) around the granuloma were identified. Analyses revealed upregulated pathways in the granuloma corresponding to the activation of T-lymphocytes and monocytes/macrophages cytokines, the upregulation of extracellular matrix signatures, and the induction of the TGF-β signaling in the perigranuloma. A comparison between the proximal and distal muscles to the granuloma revealed an inverse correlation between the distance to the granuloma and the upregulation of cellular response to interferon-γ/α, TNF-α, IL-1,4,6, fibroblast proliferation, epithelial to mesenchymal cell transition, and the downregulation of muscle gene expression. These data shed light on the intercommunications between granulomas and the muscle tissue and provide pathophysiological mechanisms by showing that granuloma immune cells have a direct impact on proximal muscle tissue by promoting its progressive replacement by fibrosis via the expression of pro-inflammatory and profibrosing signatures. These data could possibly explain the evolution towards a state of disability for some patients.

Published
2023
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19. Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report.

Author

Pegat A, Streichenberger N, Lacoste N, Hermier M, Menassa R, Coudert L, Theuriet J, Froissart R, Terrone S, Bouhour F, Michel-Calemard L, Schaeffer L, and Jacquier A

Subjects
Male, Humans, Introns genetics, Mutation, Muscle Weakness genetics, Autophagy genetics, Vacuolar Proton-Translocating ATPases genetics, Muscular Diseases genetics, Muscular Diseases pathology
Abstract

X-linked Myopathy with Excessive Autophagy (XMEA) is a rare autophagic vacuolar myopathy caused by mutations in the Vacuolar ATPase assembly factor VMA21 gene; onset usually occurs during childhood and rarely occurs during adulthood. We described a 22-year-old patient with XMEA, whose onset was declared at 11 through gait disorder. He had severe four-limb proximal weakness and amyotrophy, and his proximal muscle MRC score was between 2 and 3/5 in four limbs; creatine kinase levels were elevated (1385 IU/L), and electroneuromyography and muscle MRI were suggestive of myopathy. Muscle biopsy showed abnormalities typical of autophagic vacuolar myopathy. We detected a hemizygous, unreported, intronic, single-nucleotide substitution c.164-20T>A (NM&#95;001017980.4) in intron 2 of the VMA21 gene. Fibroblasts derived from this patient displayed a reduced level of VMA21 transcripts (at 40% of normal) and protein, suggesting a pathogenicity related to an alteration of the splicing efficiency associated with an intron retention. This patient with XMEA displayed a severe phenotype (rapid weakness of upper and lower limbs) due to a new intronic variant of VMA21 , related to an alteration in the splicing efficiency associated with intron retention, suggesting that phenotype severity is closely related to the residual expression of the VMA21 protein.

Published
2022
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20. Erotomania and phenotypic continuum in a family frameshift variant of AUTS2: a case report and review.

Author

Gauld C, Poisson A, Reversat J, Peyroux E, Houdayer-Robert F, Rossi M, Lesca G, Sanlaville D, and Demily C

Subjects
Adolescent, Cytoskeletal Proteins genetics, Female, Humans, Middle Aged, Phenotype, Quality of Life, Transcription Factors genetics, Autism Spectrum Disorder genetics, Intellectual Disability genetics
Abstract

Background: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene., Case Presentation: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant., Conclusions: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research., (© 2021. The Author(s).)

Published
2021
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