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1. Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome

Author: Anne Legrand, Charline Guery, Julie Faugeroux, Erika Fontaine, Carole Beugnon, Amélie Gianfermi, Irmine Loisel-Ferreira, Marie-Christine Verpont, Salma Adham, Tristan Mirault, Juliette Hadchouel, Xavier Jeunemaitre, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Adham, Salma
Subjects: Male, Cancer Research, Aortic Rupture, Arteries, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Disease Models, Animal, Mice, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Collagen Type III, Genetics, Animals, Humans, Ehlers-Danlos Syndrome, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract: Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.
Published: 2022
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2. Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

Author: Charlotte La Fay, Pauline Heux, Anne Spraul, Marine Juzaud, Alice Hadchouel, Alexandre Fabre, Jean-Christophe Dubus, Celia Hoebeke, Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Bicêtre Hospital, 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), Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie Allergologie [CHU 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and COMBE, Isabelle
Subjects: Male, medicine.disease_cause, Bioinformatics, Liver disease, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MARS1, Hypoalbuminemia, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, Mutation, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Liver Diseases, 030305 genetics & heredity, LARS1, General Medicine, Syndrome, Phenotype, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Failure to thrive, [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, medicine.symptom, Pulmonary alveolar proteinosis, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Methionine-tRNA Ligase, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Human Phenotype Ontology, Genetics, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Gene, 030304 developmental biology, business.industry, Infant, Infantile liver failure syndrome type 1, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Failure to Thrive, tRNA synthetase deficiency, Leucine-tRNA Ligase, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, Lung Diseases, Interstitial
Abstract: Introduction Aminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1. We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms. Results The first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature. All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia. Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations. Conclusion Patients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.
Published: 2021
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3. Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Author: Marianne Burgard, George C. Hartoularos, Martin Castelle, Alice Hadchouel, Laureline Berteloot, Romain Lévy, Bénédicte Neven, Jean-Laurent Casanova, Qian Zhang, Karim Dorgham, Lucy Bizien, Chun Jimmie Ye, Hanène Abid, Tom Toin, Isabelle Melki, Peng Zhang, Nadhira Houhou-Fidouh, Paul Bastard, Emmanuelle Jouanguy, Charlotte Roy, Flore Rozenberg, Guy Gorochov, Service d'immuno-hématologie pédiatrique [CHU 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), Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de Pneumologie Allergologie [CHU Necker], University of California (UC), CHU Necker - Enfants Malades [AP-HP], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [CHU Necker], Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service de Génétique Médicale [CHU Necker], Service d'Immunologie [CHU Pitié-Salpétrière], 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), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), Gestionnaire, HAL Sorbonne Université 5, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères - - GENVIR2020 - ANR-20-CE93-0003 - AAPG2020 - VALID, Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19. - - AABIFNCOV2020 - ANR-20-CO11-0001 - COVID-19 - VALID, Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant. - - GenMIS-C2021 - ANR-21-COVR-0039 - COVID-19 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: medicine.drug_class, Viremia, Monoclonal antibody, Antibodies, Monoclonal, Humanized, Virus, Neutralization, 03 medical and health sciences, Immunocompromised Host, 0302 clinical medicine, Interferon, medicine, Genetics, Humans, 030304 developmental biology, Blood type, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, business.industry, SARS-CoV-2, COVID-19, interferon, Viral Load, Biological Sciences, medicine.disease, Antibodies, Neutralizing, Interferon-Stimulated Gene Factor 3, gamma Subunit, 3. Good health, Upper respiratory tract infection, Child, Preschool, inherited primary immunodeficiency, Immunology, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, RNA-seq, business, Viral load, 030215 immunology, medicine.drug
Abstract: Significance Life-threatening COVID-19 pneumonia can be caused by rare inborn errors of type I interferon (IFN) immunity, or by autoantibodies neutralizing IFN-α2 or IFN-ω. In 2018, we reported a girl with critical influenza pneumonia due to inherited IRF9 deficiency, a component of the ISGF-3 transcription factor. We report the course of COVID-19 in the same patient. She was admitted on day 1 of upper respiratory tract infection with viremia. Administration of SARS-CoV-2–specific neutralizing monoclonal antibodies on day 2 prevented the development of pneumonia. SARS-CoV-2–specific monoclonal antibodies were sufficient to overcome a lack of ISGF-3– and IRF9-dependent type I and type III IFN immunity to the virus. They should be considered in selected children at high risk of life-threatening COVID-19., We describe an unvaccinated child at risk for life-threatening COVID-19 due to an inherited deficiency of IRF9, which governs ISGF-3–dependent responses to type I and III interferons (IFN). She was admitted, with a high nasal SARS-CoV-2 load on day 1 of upper respiratory tract infection. She was viremic on day 2 and received casirivimab and imdevimab. Her clinical manifestations and viremia disappeared on days 3 and 4, respectively. Circulating SARS-CoV-2 virus induced the expression of IFN-stimulated genes in leukocytes on day 1, whereas the secretion of blood type I IFNs, which peaked on day 4, did not. Antibody-mediated SARS-CoV-2 neutralization is, therefore, sufficient to overcome a deficiency of antiviral IFNs.
Published: 2021
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4. Factors Associated with Asthma Severity in Children: Data from the French COBRAPed Cohort

Author: Muriel Le Bourgeois, Guillaume Lezmi, Raphaël Chiron, Marie-Alexandra Alyanakian, Jacques de Blic, Jacques Brouard, Valérie Jolaine, Isabelle Pin, Sylvain Blanchon, Léa Roditis, Christophe Delacourt, C. Mordacq, Emmanuelle Bosdure, Mathieu Pellan, Véronique Houdoin, Graziella Mingardi, David Drummond, Irina Badiu-Decleyre, Patrick Berger, Rola Abou-Taam, V. Jubin, S. Vrielynck, Caroline Tournegros, Sylvie-Anne André Gomez, Julie Mazenq, Marie-Christine Werck Gallois, Stéphanie Wanin, Philippe Reix, Naïm Bouazza, Stephane Debelleix, Camille Ohlmann, Antoine Deschildre, Caroline Thumerelle, Alice Hadchouel-Duvergé, Guillaume Simon, Marie Noelle Lebras, Laurent Béghin, Lucienne Chatennoud, Stéphanie Lejeune, Isabelle Cabon, Patricia El Boustany, Jean-Christophe Dubus, Cecile Bonnel, Valérie Siao, Michael Fayon, Christophe Marguet, Laure Delbecque, Lisa Giovannini-Chami, Marine Servat, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de Pneumologie et d'Allergologie Pédiatriques, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), AP-HP Hôpital universitaire Robert-Debré [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Asthma severity, Disease, Dermatitis, Atopic, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Food allergy, Risk Factors, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Child, ComputingMilieux_MISCELLANEOUS, Asthma, Respiratory Sounds, business.industry, Atopic dermatitis, Odds ratio, medicine.disease, 3. Good health, 030228 respiratory system, Child, Preschool, Cohort, Observational study, business, Food Hypersensitivity
Abstract: Background Severe asthma (SA) in children is a complex, heterogeneous disease, associated with a considerable burden. However, factors influencing asthma severity are poorly described and may differ according to age. Objective To determine whether factors associated with asthma severity differ between preschoolers with severe recurrent wheeze (SRW) and school-age children with SA. Methods Data from the French multicenter prospective observational cohort of preschool (3-6 years) children with SRW and nonsevere recurrent wheeze (NSRW) and school-age (7-11 years) children with SA and nonsevere asthma (NSA) (Pediatric Cohort of Bronchial Obstruction and Asthma) were analyzed. Results A total of 131 preschool children (92 SRW and 49 NSRW) and 207 school-age children (92 SA and 115 NSA) were included. In both univariable and multivariable analysis, SRW was associated with second-hand smoke exposure (multivariable analysis: odds ratio [95% CI], 29.8 [3.57-3910]) and exposure to mold/dampness at home (multivariable analysis: odds ratio [95% CI], 4.22 [1.25-18.2]) compared with NSRW. At school-age, history of atopic dermatitis and food allergy was more frequent in children with SA than in those with NSA. Multivariable analysis confirmed that SA was associated with a history of food allergy (odds ratio [95% CI], 5.01 [2.23-11.9]). Conclusions Our data suggest that factors influencing asthma severity may differ according to age. In preschool children with SRW, second-hand smoke and exposure to mold are predominant, whereas associated allergic disorders are mainly involved in SA at school-age.
Published: 2021
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5. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Author: Olivier Brocq, Pere Soler-Palacín, Jérôme Sirvente, Brigitte Bader-Meunier, Rawane Dagher, Naoki Kitabayashi, Laureline Berteloot, Sophie Willcocks, Nadia Jeremiah, Laura Barnabei, Stefano Volpi, Eline Van Aerde, Sylvain Breton, Damien Chan, Alice Hadchouel, Vincent Bondet, Eric Jeziorski, Despina Moshous, Antonella Insalaco, Jean-Christophe Dubus, Thierry Jo Molina, Isabelle Melki, Nathalie Stremler-Le Bel, Stéphane Blanche, Marie-Anne Morren, Alain Fischer, Mireia Lopez-Corbeto, Gillian I. Rice, Marie-Louise Frémond, Carine Wouters, Yanick J. Crow, Séverine Feuillet-Soummer, Jacques G. Rivière, Françoise Mazingue, Violaine Bresson, Bénédicte Neven, Alexandre Belot, Mathieu Fusaro, Guillaume Thouvenin, Darragh Duffy, Frédéric Rieux-Laucat, Caroline Thumerelle, Luis Seabra, Marco Gattorno, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'immuno-hématologie pédiatrique [CHU 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), Service de Pneumologie Allergologie [CHU Necker], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de radiologie pédiatrique [CHU Necker], AP-HP Hôpital universitaire Robert-Debré [Paris], Urgences pédiatriques [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, 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), Institut Pasteur [Paris], Immunologie Translationnelle - Translational Immunology lab, Hôpital Princesse Grace [Monaco], Women’s and Children’s Hospital [Adelaide], CHU Notre Dame des Secours [Jbeil], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre chirurgical Marie Lannelongue, CHU Necker - Enfants Malades [AP-HP], IRCCS Istituto Giannina Gaslini [Genoa, Italy], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospitals Leuven [Leuven], Lausanne University Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Queensland Children's Hospital, Partenaires INRAE, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service de pathologie [CHU Necker], Collège de France (CdF (institution)), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. Crow and D. Duffy acknowledge the National Research Agency (France) (grant CE17001002)., The authors wish to thank the patients and their families for their cooperation in this study. The authors are grateful to Elvira Duchesne (NP) and Samira Plassart (PhD) for their very helpful technical assistance. They thank Thomas Blauwblomme (MD, PhD, Neurosurgery Unit, Necker Hospital, Paris, France) for providing CSF from children with idiopathic hydrocephalus., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut Pasteur [Paris] (IP), Centre Chirurgical Marie Lannelongue (CCML), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Adolescent, Late onset, Interstitial lung disease, Vasculopathy, Systemic inflammation, Gastroenterology, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Lymphopenia, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Vascular Diseases, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Child, Type I interferonopathy, Immunodeficiency, Inflammation, STING1, JAK inhibitors, business.industry, Infant, Membrane Proteins, medicine.disease, 3. Good health, Polyarthritis, 030228 respiratory system, Failure to thrive, Mutation, Aicardi–Goutières syndrome, medicine.symptom, Stimulator of interferon genes, business, Lung Diseases, Interstitial
Abstract: BACKGROUND: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).OBJECTIVE: To describe a cohort of patients with SAVI.METHODS: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.CONCLUSION: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
Published: 2021
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6. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Author: Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), 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)-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), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Immunology, Central nervous system, Alpha interferon, Aicardi-Goutières syndrome, cerebrospinal fluid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medical microbiology, Downregulation and upregulation, systemic lupus erythematosus, Interferon, Humans, Immunology and Allergy, Medicine, Child, Retrospective Studies, business.industry, Infant, Interferon-alpha, medicine.disease, 3. Good health, Hydrocephalus, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Organ Specificity, Case-Control Studies, Child, Preschool, Interferon Type I, Mutation, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, STING-associated vasculopathy with onset in infancy, business, 030215 immunology, medicine.drug
Abstract: International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
Published: 2021
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7. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author: Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de 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 Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, 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), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], 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), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], 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), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract: Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
Published: 2020
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8. Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia: over expression of Spock2 and altered lung development

Author: Hadchouel, Alice, Franco-Montoya, Marie-Laure, Guérin, Sophie, Do Cruzeiro, Marcio, Lhuillier, Mickael, Ribeiro Baptista, Bruno, Boyer, Laurent, Lanone, Sophie, Delacourt, Christophe, Service de Pneumologie Allergologie [CHU 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), Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - GEIC2O/'Genetic and Environmental Interactions in COPD, Cystic fibrosis and Other (rare) respiratory diseases' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), 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 Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Lanone, Sophie
Subjects: transgenic model, Spock2, bronchopulmonary dysplasia, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, respiratory system, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lung development
Abstract: International audience; SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.
Published: 2020
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9. Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia: over expression of Spock2 and altered lung development

Author: Hadchouel, Alice, Franco-Montoya, Marie-Laure, Guérin, Sophie, Do Cruzeiro, Marcio, Lhuillier, Mickael, Ribeiro Baptista, Bruno, Boyer, Laurent, Lanone, Sophie, Delacourt, Christophe, Service de Pneumologie Allergologie [CHU 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), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université de Paris (UP), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), 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 de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: transgenic model, bronchopulmonary dysplasia, Spock2, respiratory system, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lung development
Abstract: International audience; SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.
Published: 2020
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10. Sévérité de l’hypertension hyperkaliémique familiale causée par les mutations de CUL-3

Author: Chloé Rafael, Juliette Hadchouel, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), CNRS ERL 8228 - Laboratoire de physiologie rénale et tubulopathies, 75006, Paris, France. (TIR), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], General Medicine, 030217 neurology & neurosurgery, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience; No abstract available
Published: 2020
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11. Guide pour le recueil et le traitement des signalements relatifs à l'intégrité scientifique Réseau des référents à l'intégrité scientifique

Author: Ghislaine Filliatreau, Didier Chollet, Michèle Hadchouel, Catherine Labbé-Jullié, Marc Léger, Blandine Mallet-Bricout, Elisabeth Merlen, Emmanuel Picavet, Rochet Béatrice, Alexandre Serres, Réseau des référents à l'intégrité scientifique (RESINT), Composition du groupe de travail « Procédures » Ghislaine Filliatreau (coordination), déléguée à l'intégrité scientifique (Inserm), Didier Chollet, référent à l’intégrité scientifique (Université Rouen-Normandie), Michelle Hadchouel, membre du Conseil de l'intégrité scientifique, co-animatrice de RESINT, Catherine Labbé-Jullié, référente à l’intégrité scientifique (Université Paris-Descartes), Marc Léger, référent à l’intégrité scientifique (CEA), Blandine Mallet-Bricout, référente intégrité scientifique (Université de Lyon Jean Moulin-Lyon 3), Elisabeth Merlen, référente à l'intégrité scientifique (IFP Energies nouvelles), Emmanuel Picavet, référent à l'intégrité scientifique (Université Paris 1 Panthéon-Sorbonne), Béatrice Rochet, déléguée à la déontologie et l'intégrité (Ifremer), Alexandre Serres, référent à l’intégrité scientifique (Université Rennes 2), Rémy Mosseri, référent à l'intégrité scientifique (CNRS), a été associé ce travail., and Duchange, Nathalie
Subjects: guide, intégrité scientifique, procédures, principes, recommandations, [SDV.ETH] Life Sciences [q-bio]/Ethics, [SDV.ETH]Life Sciences [q-bio]/Ethics
Abstract: Ce guide a été rédigé par un groupe de travail du Réseau des référents à l’intégrité scientifique(RESINT), avec pour premier objectif d’aider chaque référent à l’intégrité scientifique (RIS1) àmettre en oeuvre, dans son établissement ou organisme, une procédure de réponse auxsignalements de manquements à l'intégrité scientifique qui soit conforme aux bonnes pratiques ence domaine, notamment en adaptant pour son établissement ou organisme les dispositions qui ysont proposées. Un second objectif est de faciliter la coopération entre RIS, étant rappelé quecertains des dossiers qu’ils ont à traiter concernent plusieurs opérateurs de recherche(personnels de recherche employés ou financés par des opérateurs différents ou travaillant dansdes unités mixtes, éventuellement à des moments différents, etc.) et nécessitera donc uneinstruction commune.Le guide propose, à cette fin, une série de recommandations conformes aux principales sourcesofficielles, françaises et européennes, relatives à l’intégrité scientifique pour aider chaqueétablissement ou organisme à établir des procédures adaptées à ses besoins. Enfin, il est destiné àévoluer en fonction des retours d'expériences partagés par les membres du réseau.
Published: 2018

12. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis

Author: Jennifer Baraka-Vidot, María Chávez-Canales, Régine Chambrey, Juliette Hadchouel, Alexia Pillot, Maximilien Jayat, Yusuke Kumai, Karen I. López-Cayuqueo, Christelle Soukaseum, Dominique Eladari, Xavier Jeunemaitre, Francesco Trepiccione, Véronique Baudrie, Cara Büsst, Pascal Houillier, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité des maladies rénales et métaboliques [Hôpital Européen Georges-Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'Etude sur l'Inflammation Chronique et l'Obésité (GEICO), Université de La Réunion (UR), University of Edinburgh, López-Cayuqueo, Karen I, Chavez-Canales, Maria, Pillot, Alexia, Houillier, Pascal, Jayat, Maximilien, Baraka-Vidot, Jennifer, Trepiccione, Francesco, Baudrie, Véronique, Büsst, Cara, Soukaseum, Christelle, Kumai, Yusuke, Jeunemaître, Xavier, Hadchouel, Juliette, Eladari, Dominique, Chambrey, Régine, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, pendrin, Pseudohypoaldosteronism, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Sodium Chloride, Renal tubular acidosis, Gene Knockout Techniques, Mice, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, biology, Chemistry, Reabsorption, Acidosis, Renal Tubular, WNK4, Up-Regulation, medicine.anatomical_structure, Nephrology, Sulfate Transporters, renal tubular acidosi, medicine.medical_specialty, hypertension, Mutation, Missense, Mice, Transgenic, Protein Serine-Threonine Kinases, 03 medical and health sciences, intercalated cell, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Distal convoluted tubule, Kidney Tubules, Collecting, Sodium-Bicarbonate Symporters, Metabolic acidosis, Pendrin, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Renal Elimination, 030104 developmental biology, Endocrinology, Gordon syndrome, biology.protein, Potassium, familial hyperkalemic hypertension, Homeostasis
Abstract: Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in β-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis. Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in beta-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.
Published: 2018
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13. Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4

Author: Christelle Soukaseum, Chloé Rafael, Véronique Baudrie, Perrine Frère, Juliette Hadchouel, Hadchouel, Juliette, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Sorbonne Université (SU), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm), the Fondation pour la Recherche pour l’Hypertension Artérielle, the Agence Nationale pour la Recherche (ANR-12-ISVS1-0001-01/New-BP-KIT). CR received a fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Pseudohypoaldosteronism, lcsh:Medicine, Protein Serine-Threonine Kinases, medicine.disease_cause, Article, Mice, 03 medical and health sciences, WNK Lysine-Deficient Protein Kinase 1, Ubiquitin, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Gene Knock-In Techniques, lcsh:Science, Crosses, Genetic, Mutation, Multidisciplinary, biology, Chemistry, Kinase, urogenital system, lcsh:R, medicine.disease, WNK1, WNK4, Disease Models, Animal, 030104 developmental biology, Endocrinology, biology.protein, Phosphorylation, lcsh:Q, Cotransporter
Abstract: International audience; Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1 +/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases. We show that WNK1 +/ FHHT :SPAK 243A/243A mice display an intermediate phenotype, between that of control and SPAK 243A/243A mice, with normal blood pressure but hypochloremic metabolic alkalosis. NCC abundance and phosphorylation levels also decrease below the wild-type level in the double-mutant mice but remain higher than in SPAK 243A/243A mice. This is different from what was observed in WNK4-FHHt mice in which SPAK inactivation completely restored the phenotype and NCC expression to wild-type levels. Although these results confirm that FHHt caused by WNK1 mutations is dependent on the activation of SPAK, they suggest that WNK1 and WNK4 play different roles in the distal nephron. Familial Hyperkaliaemic Hypertension (FHHt), also known as Gordon's syndrome or Pseudohypoaldosteronism type II (PHAII), is a rare genetic form of hypertension associated with hyperkalemia and metabolic hyperchlo-remic acidosis (OMIM #145260) 1. All these symptoms are corrected by thiazide diuretics, which inhibit the activity of the Na +-Cl − transporter NCC, encoded by the SLC12A3 gene 1. FHHt is caused by mutations in one of at least four genes: WNK1 [With No lysine (K) 1], WNK4, KLHL3 (Kelch-Like family member 3), and CUL3 (cullin-3) 2-4. The associated proteins belong to the same regulatory pathway, as WNK1 and WNK4 are recruited by KLHL3 for ubiquitination by the Cul3-E3 RING-type ubiquitin-ligase complex 5. The sensitivity of patients to thiazide diuretics strongly suggested that FHHt is mainly caused by a gain of activity of NCC in the distal nephron. The role of NCC in regulating blood pressure has been established by the discovery of inactivating mutations of the SLC12A3 gene, which cause Gitelman's syndrome, an inherited disorder that is the mirror image of FHHt, with arterial hypotension, renal salt wasting and hypokalemic metabolic alkalosis (OMIM #263800) 6,7. Therefore, several studies focused on the mechanisms underlying the regulation of NCC by WNK1 and WNK4. In vitro studies have demonstrated that the WNKs activate two kinases, SPAK (Ste20-related Proline/ Alanine-rich Kinase) and OSR1 (oxidative stress-responsive kinase 1) 8 , which can in turn phosphorylate and activate NCC 9. SPAK and OSR1 can also activate the Na +-K +-2Cl − cotransporters, NKCC1 and NKCC2, and inhibit the K +-Cl − cotransporters, KCC1-4 10. In vivo, the expression and phosphorylation of NCC is reduced
Published: 2018
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14. Decreased pulmonary capillary volume in adolescents born very preterm

Author: Muriel Le Bourgeois, Stéphane Marret, Jean-Christophe Rozé, David Drummond, Christophe Delacourt, Jessica Rousseau, Pierres-Yves Ancel, Alice Hadchouel, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Universités (COMUE)
Subjects: medicine.medical_specialty, Adolescent, MEDLINE, Gestational Age, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Medicine, Humans, 030212 general & internal medicine, Lung, enfant, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Obstetrics, Infant, Newborn, General Medicine, Capillary volume, Very preterm, 030228 respiratory system, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Premature Birth, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2019
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15. Double Knockout of the Na + -Driven Cl − /HCO 3 − Exchanger and Na + /Cl − Cotransporter Induces Hypokalemia and Volume Depletion

Author: Régine Chambrey, Christian A. Hübner, Anne Sinning, Maximilien Jayat, Karen I. López-Cayuqueo, Stéphanie Baron, R. Todd Alexander, Nicolas Cornière, Juliette Hadchouel, Dominique Eladari, Nikita Radionov, Francesco Trepiccione, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centro de Estudios Científicos (CECs), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), University of Alberta, Centre National de la Recherche Scientifique (CNRS), Hadchouel, Juliette, Sinning, Anne, Radionov, Nikita, Trepiccione, Francesco, López Cayuqueo, Karen I, Jayat, Maximilien, Baron, Stéphanie, Cornière, Nicola, Alexander, R. Todd, Eladari, Dominique, Hübner, Christian A, and Chambrey, Régine
Subjects: 0301 basic medicine, Epithelial sodium channel, medicine.medical_specialty, hypertension, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], diuretic, 030232 urology & nephrology, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Internal medicine, medicine, hypokalemia, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Chloride-Bicarbonate Antiporters, Thiazide, Mice, Knockout, Blood Volume, biology, Animal, Chemistry, Chloride-Bicarbonate Antiporter, General Medicine, Pendrin, Hypokalemia, diuretics, Up-Regulation, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Basic Research, 030104 developmental biology, Endocrinology, Nephrology, biology.protein, medicine.symptom, Cotransporter, Homeostasis, medicine.drug
Abstract: International audience; We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl-/HCO3- exchanger pendrin and the Na+-driven Cl-/2HCO3- exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+ balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+ balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na+ homeostasis and provide evidence that the Na+/Cl- cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K+ concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+-activated K+ channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+ concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients.
Published: 2017
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16. Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study

Author: Catherine Arnaud, Jessica Rousseau, Laure Couderc, Alice Hadchouel, Jean-Christophe Rozé, Adèle Bellino, Christophe Delacourt, Marie Mittaine, Stéphane Marret, Pierre-Yves Ancel, Marie Verstraete, Didier Pinquier, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire sols, solides, structures - risques [Grenoble] (3SR ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), INSERM, U1027, Toulouse, France., Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), 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), Aix Marseille Université (AMU), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11), Domaines Océaniques (LDO), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Observatoire des Sciences de l'Univers-Institut d'écologie et environnement-Centre National de la Recherche Scientifique (CNRS), Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire sols, solides, structures - risques [Grenoble] (3SR), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre National de la Recherche Scientifique (CNRS)-Institut d'écologie et environnement-Observatoire des Sciences de l'Univers-Université de Brest (UBO)-Institut national des sciences de l'Univers (INSU - CNRS)
Subjects: Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Adolescent, Term Birth, [SDV]Life Sciences [q-bio], 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Forced Expiratory Volume, Humans, Medicine, Prospective Studies, Respiratory system, Child, ComputingMilieux_MISCELLANEOUS, Lung function, Bronchopulmonary Dysplasia, Respiratory Sounds, Asthma, business.industry, Confounding, paediatric asthma, medicine.disease, 3. Good health, respiratory tract diseases, Very preterm, 030104 developmental biology, Breath Tests, 030228 respiratory system, Bronchopulmonary dysplasia, Case-Control Studies, Child, Preschool, Cohort, Premature Birth, Female, Nitrogen Oxides, France, business, paediatric lung disaese, Cohort study
Abstract: Prematurity and bronchopulmonary dysplasia (BPD) affect long-term lung function. We studied the respiratory outcome of adolescents born very preterm and controls from the Etude EPIdémiologique sur les Petits Ages Gestationnels cohort and analysed their current lung function in relation to asthma symptoms (categorised in three age groups) from birth. In models including BPD, asthma at each age and confounding factors in the preterm group, BPD and preschool wheeze were the only independent variables associated with FEV1. Preschool wheeze is an independent factor associated with FEV1 impairment in adolescents born very preterm. These results highlight the need for optimal management of early respiratory symptoms in preterm-born infants.Trial registration numberResults, NCT01424553.
Published: 2018
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17. Successful haematopoietic stem cell transplantation in a case of pulmonary alveolar proteinosis due to GM-CSF receptor deficiency

Author: Cécile Pochon, Christophe Delacourt, Bénédicte Neven, Alessandra Magnani, Alice Hadchouel, Despina Moshous, Coralie Briand, Laureline Berteloot, Alain Fischer, Stéphane Blanche, Cyril Schweitzer, Julie Bruneau, Jacques de Blic, Guilhem Cros, Marie-Louise Frémond, Marina Cavazzana, Cécile Bonnet, and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, medicine.medical_treatment, Hematopoietic stem cell transplantation, Pulmonary Alveolar Proteinosis, 03 medical and health sciences, 0302 clinical medicine, Oxygen therapy, medicine, Humans, X chromosome, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, business.industry, Hematopoietic Stem Cell Transplantation, Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hypoxia (medical), medicine.disease, 3. Good health, Transplantation, Haematopoiesis, 030104 developmental biology, Bronchoalveolar lavage, 030228 respiratory system, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Female, medicine.symptom, Pulmonary alveolar proteinosis, business
Abstract: Cyril Schweitzer (CS) : A 1.5-year-old girl was referred to the Paediatric Pneumology Department of the University Hospital of Nancy, France, for progressive tachypnoea and hypoxia. She suffered from intrauterine growth retardation, and was born prematurely at 31 weeks’ gestation; birth weight: 1.160 kg (≤2 SD); birth length: 37 cm (≤2 SD). The patient presented with acute respiratory distress syndrome at birth, requiring treatment with a dose of surfactant, 9 days of mechanical ventilation and 8 weeks of oxygen therapy. On arrival to our centre, she was dyspnoeic on exertion and oxygen saturations were between 91% and 94%. Further investigations included a high-resolution CT scan and a bronchoalveolar lavage (BAL). Laureline Berteloot (LB) and Julie Bruneau (JB) : CT imaging of the chest revealed a ‘crazy paving’ pattern whereas analysis of BAL fluid failed to identify any underlying disease. CS : Hypoxia transiently improved after initiation of inhaled corticosteroids and antireflux therapy but relapsed after a few months, so that a second BAL was performed. JB : The second BAL fluid revealed the presence of extracellular lipid and protein deposits and foamy alveolar macrophages. CS and Cecile Bonnet (CeB) : These abnormalities led to a diagnosis of pulmonary alveolar proteinosis (PAP) at the age of 2.6 years, which was confirmed by genetic testing; complex chromosome abnormalities were detected, with (1) deletion of CSF2RA and CRLF2 on the X chromosome inherited from the mother, and (2) a de novo rearrangement of the paternal X chromosome, resulting in loss of both CSF2RA alleles.1 CS, Christophe Delacourt (CD) and Jacques De Blic (JDB) : Recessive mutations in the α or β subunits of the granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R, encoded respectively by CSF2RA and CSF2RB ) cause two subtypes of hereditary PAP.2 Impairment of GM-CSF-dependent surfactant clearance by alveolar macrophages leads to the progressive accumulation of surfactant in the alveolar space …
Published: 2018
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18. Mutations in MARS identified in a specific type of pulmonary alveolar proteinosis alter methionyl-tRNA synthetase activity

Author: Jacques de Blic, Marc Mirande, Martine Comisso, Alice Hadchouel, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblages supramoléculaires et traduction (MARS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Models, Molecular, Protein Conformation, alpha-Helical, 0301 basic medicine, RNA, Transfer, Met, pulmonary alveolar proteinosis, [SDV]Life Sciences [q-bio], Genetic Vectors, Mutant, Gene Expression, Aminoacylation, Methionine-tRNA Ligase, Biochemistry, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, Methionine, Escherichia coli, medicine, Animals, Humans, Missense mutation, Protein Interaction Domains and Motifs, Amino Acid Sequence, Translation factor, Cloning, Molecular, aminoacylation kinetics, Molecular Biology, chemistry.chemical_classification, Binding Sites, Sequence Homology, Amino Acid, Chemistry, methionyl-tRNA synthetase, Cell Biology, medicine.disease, Molecular biology, Recombinant Proteins, Cytosol, 030104 developmental biology, Enzyme, Mutation, Mutagenesis, Site-Directed, Protein Conformation, beta-Strand, Transfer RNA Aminoacylation, Pulmonary alveolar proteinosis, Sequence Alignment, Protein Binding
Abstract: International audience; Biallelic missense mutations in MARS are responsible for rare but severe cases of pulmonary alveolar proteinosis (PAP) prevalent on the island of La Réunion. MARS encodes cytosolic methionyl-tRNA synthetase (MetRS), an essential translation factor. The multisystemic effects observed in patients with this form of PAP are consistent with a loss-of-function defect in an ubiquitously expressed enzyme. The pathophysiological mechanisms involved in MARS-related PAP are currently unknown. In this work, we analyzed the effect of the PAP-related mutations in MARS on the thermal stability and on the catalytic parameters of the MetRS mutants, relative to wild-type. The effect of these mutations on the structural integrity of the enzyme as a member of the cytosolic multisynthetase complex was also investigated. Our results establish that the PAP-related substitutions in MetRS impact the tRNAMet -aminoacylation reaction especially at the level of methionine recognition, and suggest a direct link between the loss of activity of the enzyme and the pathological disorders in PAP.
Published: 2018
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19. Eosinophilic Pneumonias in Children: A Review of the Epidemiology, Diagnosis, and Treatment

Author: Giovannini-Chami, Lisa, Blanc, Sibylle, Hadchouel, Alice, Baruchel, André, Boukari, Rachida, Dubus, Jean-Christophe, Fayon, Michael, Le Bourgeois, Muriel, Nathan, Nadia, Albertini, Marc, Clement, Annick, Blic, Jacques, Service de Pneumologie Allergologie pédiatriques, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de Pneumologie Allergologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie pédiatrique, CHU Bordeaux [Bordeaux], CIC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], 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 Pierre et Marie Curie - Paris 6 (UPMC), CHU Nice-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Université Nice Sophia Antipolis - Faculté de Médecine ( UNS UFR Médecine ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pneumologie Pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université Nice Sophia Antipolis (1965 - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Le centre hospitalier universitaire (CHU) Mustapha Pacha [Alger], Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: visceral larva migrans syndrome, Adolescent, Drug-Related Side Effects and Adverse Reactions, Lung Diseases, Parasitic, idiopathic acute eosinophilic pneumonia, Aspergillosis, Allergic Bronchopulmonary, pical eosinophilic pneumonia, Churg-Strauss Syndrome, respiratory system, Prognosis, Bronchoalveolar Lavage, drug-induced eosinophilic pneumonia, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Leukocyte Count, Adrenal Cortex Hormones, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, idiopathic chronic eosinophilic, Child, Preschool, Hypereosinophilic Syndrome, allergic bronchopulmonary aspergillosis, Humans, Pulmonary Eosinophilia, Child, Immunosuppressive Agents
Abstract: International audience; Pediatric eosinophilic pneumonias (EPs) are characterized by a significant infiltration of the alveolar spaces and lung interstitium by eosinophils, with conservation of the lung structure. In developed countries, EPs constitute exceptional entities in pediatric care. Clinical symptoms may be transient (Loffler syndrome), acute (1 month). Diagnosis relies on demonstration of alveolar eosinophilia on bronchoalveolar lavage, whether or not associated with blood eosinophilia. EPs are a heterogeneous group of disorders divided into: (i) secondary forms (seen mainly in parasitic infections, allergic bronchopulmonary aspergillosis, and drug reactions); and (ii) primary forms (eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, idiopathic chronic eosinophilic pneumonia, and idiopathic acute eosinophilic pneumonia). Despite their rarity, the etiological approach to EP must be well-defined as some causes can be rapidly life-threatening without initiation of the proper treatment. This approach (i) eliminates secondary forms, with comprehensive history taking and minimal biological assessment, (ii) is oriented in primary forms by the acute or chronic setting, and the existence of extrapulmonary symptoms. Treatment of primary forms has traditionally relied on corticosteroids, usually with a dramatic response. Specific treatments or the adjunction of corticosteroid-sparing treatment or immunosuppressors are currently being evaluated in order to improve the prognosis and the side effects associated with corticosteroid treatment in a pediatric setting. (C) 2015 Wiley Periodicals, Inc.
Published: 2016
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20. Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia

Author: Pierre-Henri Jarreau, Emmanuelle Bouzigon, Johanna M. Huusko, Roberto Incitti, Ines Layouni, Jacques R. Bourbon, Richard Lenclen, Claude Danan, Florence Demenais, Mikko Hallman, Alice Hadchouel, Juliana Patkai, Christophe Delacourt, Xavier Durrmeyer, Marie-Laure Franco-Montoya, INSERM U955, équipe 4, Service de Pneumologie Allergologie [CHU 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de réanimation néonatale de Créteil, CHI Créteil, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of pediatrics, Oulu University Hospital-Institute of Clinical Medicine, PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation néonatale Port-Royal, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Néonatale, CHI Poissy-Saint-Germain, Unité Fonctionnelle de Recherche Clinique, Programme Hospitalier de Recherche Clinique AOR 07 018, Assistance Publique - Hôpitaux de Paris. Hadchouel was funded by INSERM., CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), and CHU Cochin [AP-HP]
Subjects: Male, Pathology, Gene Expression, MESH : Genotype, Disease, Critical Care and Intensive Care Medicine, MESH: Animals, Newborn, MESH: Genotype, 0302 clinical medicine, Polymorphism (computer science), MESH : Female, MESH: Animals, MESH: Bronchopulmonary Dysplasia, Finland, Bronchopulmonary Dysplasia, 0303 health sciences, education.field_of_study, MESH : Rats, MESH : Animals, Newborn, MESH: Polymorphism, Single Nucleotide, MESH: Finland, MESH : Polymorphism, Single Nucleotide, Respiratory disease, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, Gestational age, MESH: European Continental Ancestry Group, MESH : Proteoglycans, 3. Good health, MESH : Infant, Premature, medicine.anatomical_structure, MESH: Proteoglycans, Female, Proteoglycans, MESH : Genome-Wide Association Study, Infant, Premature, MESH : Finland, MESH : Bronchopulmonary Dysplasia, Pulmonary and Respiratory Medicine, MESH: Infant, Premature, medicine.medical_specialty, MESH: Gene Expression, Genotype, MESH: Rats, MESH : Lung, MESH : Male, Population, Black People, MESH : Infant, Newborn, Polymorphism, Single Nucleotide, White People, Article, MESH : African Continental Ancestry Group, premature, lung, MESH : European Continental Ancestry Group, 03 medical and health sciences, 030225 pediatrics, Intensive care, medicine, Animals, Humans, Genetic Predisposition to Disease, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, development, 030304 developmental biology, Lung, MESH: Humans, business.industry, MESH : Humans, Infant, Newborn, medicine.disease, infant, MESH: Male, Rats, MESH : Gene Expression, Animals, Newborn, Bronchopulmonary dysplasia, Immunology, MESH: Genome-Wide Association Study, MESH : Genetic Predisposition to Disease, MESH : Animals, MESH: African Continental Ancestry Group, DNA microarrays, business, MESH: Female, Genome-Wide Association Study
Abstract: International audience; RATIONALE: Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility. OBJECTIVES: To identify genetic variants involved in bronchopulmonary dysplasia through a genome-wide association study. METHODS: We prospectively evaluated 418 premature neonates (gestational age
Published: 2011
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21. Idiopathic eosinophilic pneumonia in children: the French experience

Author: Jacques de Blic, Virginie Feret, François Bremont, Nadia Nathan, Jean Christophe Dubus, Thierry Leblanc, M. Albertini, Véronique Houdouin, Lisa Giovannini-Chami, Michèle Berlioz-Baudoin, Karine Morelle, Michael Fayon, Annick Clement, Alice Hadchouel, Service de Pneumologie Allergologie pédiatriques, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de Pneumologie Allergologie [CHU 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Pédiatrie - Pneumologie, Allergologie, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de pneumologie pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-CHU Marseille, CHU Bordeaux [Bordeaux], CIC - Bordeaux, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie et immunologie pédiatrique, the French Respirare® Group, CHU Nice-Hôpitaux pédiatriques de Nice CHU-Lenval, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pneumologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -CHU Marseille, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), BMC, Ed., Université Nice Sophia Antipolis (1965 - 2019) (UNS), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Idiopathic acute eosinophilic pneumonia, Eosinophilic lung disease, Interstitial lung disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, medicine, Extracorporeal membrane oxygenation, Eosinophilic pneumonia, Humans, Genetics(clinical), Pharmacology (medical), Idiopathic chronic eosinophilic pneumonia, Pulmonary Eosinophilia, Child, Idiopathic interstitial pneumonia, Genetics (clinical), Retrospective Studies, Medicine(all), [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, Retrospective cohort study, General Medicine, medicine.disease, 3. Good health, Child, Preschool, Immunology, Female, France, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, Tomography, X-Ray Computed, Bronchoalveolar Lavage Fluid, Rare disease
Abstract: International audience; BACKGROUND: Idiopathic eosinophilic pneumonia is extremely rare in children and adults. We present herein the first series describing the specificities of idiopathic chronic (ICEP) and acute (IAEP) eosinophilic pneumonia in children. METHODS: We retrospectively analyzed all cases of ICEP and IAEP in children that were retrieved from French Reference Centers for rare pediatric lung diseases. RESULTS: Five cases of pediatric ICEP were identified. Corticosteroid or immunosuppressive therapy dramatically improved the outcome in three cases. The remaining two cases had a persistent interstitial pattern with progressive development of cystic airspace lesions. Three cases of IAEP in adolescents were reported, with one requiring four days of extracorporeal membrane oxygenation. CONCLUSION: ICEP is a rare disease with a polymorphic clinical presentation in children. We identified patients with persistent interstitial patterns progressing to cystic airspace regions, for which the boundaries with idiopathic interstitial pneumonias are difficult to establish. We therefore propose a specific pediatric definition and classification algorithm. IAEP in children remains an inflammatory reaction of the lung to an acute toxic exposure, mainly tobacco, as in adults. International studies are required to comprehensively assess the various clinical forms of the disease as well as the appropriate therapeutic regimens.
Published: 2014
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22. Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?

Author: Bruno Toupance, Florence Lacaille, Laureline Berteloot, Virginie Verkarre, Jacques de Blic, Michel Renouil, Malek Louha, Françoise Darcel, Mélinée Linard, Jean-Pierre Rivière, Alice Hadchouel, Laurent Enaud, Matthias Griese, Liliane Boccon-Gibod, Aurore Coulomb, Christophe Delacourt, Vincent Boulay, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de radiologie pédiatrique [CHU 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), Gastro-Entérologie, Hépatologie et Nutrition pédiatriques (CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Service de neurologie, CHR Réunion, Pulmonology, University Childrens Hospital, Haunersches Kinderspital, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Eco-Anthropologie et Ethnobiologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Géosciences Océan (LGO), Université de Bretagne Sud (UBS)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie Allergologie [CHU Necker], Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), Gastroentérologie-Hépatologie et Nutrition Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Institut Français de Recherche pour l'Exploitation de la Mer - Brest (IFREMER Centre de Bretagne), and Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pediatrics, medicine.medical_specialty, Cirrhosis, [SDV]Life Sciences [q-bio], Pulmonary Alveolar Proteinosis, Pulmonary fibrosis, Liver disorder, 03 medical and health sciences, Liver disease, 0302 clinical medicine, medicine, Humans, Genetics(clinical), Pharmacology (medical), Child, Survival rate, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Retrospective Studies, 030304 developmental biology, Medicine(all), 0303 health sciences, business.industry, Research, Respiratory disease, Infant, Retrospective cohort study, General Medicine, medicine.disease, Pedigree, 3. Good health, Radiography, 030228 respiratory system, Child, Preschool, Female, France, business, Pulmonary alveolar proteinosis
Abstract: Background Pulmonary alveolar proteinosis (PAP) is very rare in children. Only a few small series have been published, with little information about long-term progression. The objective of our study was to describe the clinical, radiological and pathological features, and the long-term course of PAP in a cohort of 34 children from La Réunion Island. Methods Data were retrospectively collected from medical files. Radiological and pathological elements were reviewed by two pediatric radiologists and three pathologists, respectively. Results Thirteen cases were familial and 32/34 (94%) cases were family connected. Disease onset occurred in the first six months of life in 82% of the patients. Thoracic computed tomography scans showed the typical “crazy-paving” pattern in 94% of cases. Respiratory disease was associated with a liver disorder, with the detection of liver enlargement at diagnosis in 56% of cases. The course of the disease was characterized by frequent progression to chronic respiratory insufficiency, accompanied by the appearance of cholesterol granulomas and pulmonary fibrosis. Overall prognosis was poor, with a mortality of 59% and an overall five-year survival rate from birth of 64%. Whole-lung lavages were performed in 21 patients, with no significant effect on survival. Liver disease progressed to cirrhosis in 18% of children, with no severe complication. Conclusions PAP in children from la Réunion Island is characterized by an early onset, associated liver involvement, poor prognosis and frequent progression to lung fibrosis, despite whole-lung lavages treatment. The geographic clustering of patients and the detection of many familial links between most of the cases strongly suggest a genetic etiology, with an autosomal recessive mode of inheritance.
Published: 2014
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23. FGF10 Signaling differences between type I pleuropulmonary blastoma and congenital cystic adenomatoid malformation

Author: Jean-Luc Rittie, Jean-Christophe Fournet, Christophe Delacourt, Virginie Verkarre, Caroline Rambaud, Alice Hadchouel, Guillaume Lezmi, Marie-Christine Copin, Alexandra Benachi, Shamila Vibhushan, Naziha Khen-Dunlop, Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomie et de Cytologie Pathologiques, Service de Chirurgie Viscérale Pédiatrique, Service d'Anatomie Pathologique et Médecine Légale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Institute de Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pneumologie Allergologie Pédiatrique et Mucoviscidose, Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Service de Gynécologie-Obstétrique et Médecine de la Reproduction, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], The study was funded by a grant from Programme Hospitalier de Recherche Clinique - PHRC AOR 11 025 (Ministère de la Santé)., Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches], Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre hospitalier Felix Guyon (Saint-Denis), and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère
Subjects: Male, Pathology, medicine.medical_specialty, Lung malformation, Congenital cystic adenomatoid malformation, Pleuropulmonary blastoma, [SDV.GEN] Life Sciences [q-bio]/Genetics, Fibroblast growth factor, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Cystic Adenomatoid Malformation of Lung, Congenital, medicine, Humans, Genetics(clinical), Pharmacology (medical), Hedgehog Proteins, Sonic hedgehog, Receptor, Fibroblast Growth Factor, Type 2, Children, Genetics (clinical), Medicine(all), [SDV.GEN]Life Sciences [q-bio]/Genetics, FGF10, Lung, biology, Research, Infant, Newborn, Infant, General Medicine, respiratory system, Fibroblast growth factor 10, medicine.disease, Immunohistochemistry, respiratory tract diseases, Cystic lung disease, Pulmonary Blastoma, stomatognathic diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, biology.protein, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: Background Type I pleuropulmonary blastoma (PPB) and congenital cystic adenomatoid malformation of the lung (CCAM) are cystic lung diseases of childhood. Their clinical and radiological presentations are often similar, and pathologic discrimination remains difficult in many cases. As a consequence, type I PPB and CCAM are frequently confused, leading to delayed adequate management for type I PPB. Recent studies have suggested a role for fibroblast growth factor (FGF) 10 signal pathway in CCAM pathogenesis. The objective of our study was to determine whether FGF10 signaling differs between CCAM and type I PPB. Methods Immunohistochemical studies were performed for expression of FGF10, its receptor FGFR2b, and its inhibitor sonic hedgehog (SHH) in focal type I PPB (n=6), CCAM type I (n=7), CCAM type II (n=7), and control lungs (n=5). Results FGF10, FGFR2b, and SHH expressions differed markedly between type I PPB and both types of CCAM. Type I and type II CCAM cystic walls expressed FGF10, FGFR2b, and SHH, whereas staining was absent or poor in type I PBB cystic walls. Expression of FGF10, FGFR2b, and SHH did not differ between CCAM cystic walls and control airway walls. Conclusions These findings show that immunohistochemistry with FGF10, FGFR2b, or SHH could be useful in differentiating CCAM from type I PPB, when a child presents with a focal cystic lung lesion. The absence of strong expression of FGF10, FGFR2b, and/or SHH makes the diagnosis of CCAM very doubtful.
Published: 2013
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24. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

Author: Daniel Trujillano, Patrick Niaudet, Amélie Bonnefond, Xavier Jeunemaitre, Pascal Houillier, Olivier Sand, Mark J. Caulfield, Geneviève Beaurain, Stéphanie Miserey-Lenkei, Paul Landais, Robert J. Unwin, Georg Ehret, Chebel Mourani, Olivier Chabre, Vincent L.M. Esnault, Corinne Isnard Bagnis, Christophe Simian, Juliette Hadchouel, Patrick Bruneval, Stephan Ossowski, Béatrice Fiquet, Christelle Soukaseum, Hélène Louis-Dit-Picard, Christel Thauvin, Emmanuelle Vidal-Petiot, Julien Barc, Olena Pylypenko, Steven D. Soroka, Nabila Bouatia-Naji, Michel Delahousse, Philippe Froguel, Jean-Jacques Schott, Xavier Estivill, Jens Koenig, Chantal Mandet, Vincent Probst, Martin Konrad, Françoise Broux, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Mécanismes moléculaires du transport intracellulaire, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Motilité structurale, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université libre de Bruxelles (ULB), Service Génétique, Union nationale des coopératives d’élevage et d’insémination animale (UNCEIA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'endocrinologie, CHU Grenoble-Hôpital Michallon, Service de transplantation rénale, Hôpital Foch [Suresnes], Service de néphrologie, Centre Hospitalier Universitaire de Nice (CHU Nice), Pharmaceut, Med & Sci Affairs, Novartis, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Children's Hospital, Munster, Westfälische Wilhelms-Universität Münster (WWU), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), UFR de médecine (Université de Bourgogne), Université de Bourgogne (UB), Royal Free and University College Medical School, Center for Nephrology, Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Universitat Pompeu Fabra [Barcelona] (UPF), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Ehret, Georg Benedikt, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie [CHU Pitié-Salpêtrière], 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), Unité de recherche de l'institut du thorax (ITX-lab), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université Libre de Bruxelles [Bruxelles] (ULB), Union Nationale des Coopératives Agricoles d'Elevage et d'Insémination Animale, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Médicale, Hopital, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Universitat Pompeu Fabra [Barcelona]
Subjects: Male, Carrier Proteins/genetics, Pseudohypoaldosteronism/genetics/metabolism/physiopathology, Pseudohypoaldosteronism, [SDV]Life Sciences [q-bio], Blood Pressure, 030204 cardiovascular system & hematology, Nephrons/metabolism, Kidney, 0302 clinical medicine, Missense mutation, Child, ComputingMilieux_MISCELLANEOUS, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, biology, Microfilament Proteins, Middle Aged, WNK1, Phenotype, Sodium Chloride Symporters, WNK4, Ubiquitin ligase, Female, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, Blood Pressure/genetics, Ion Transport/genetics, Molecular Sequence Data, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Amino Acid Sequence, Sodium Chloride Symporters/genetics/metabolism, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Ion Transport, Base Sequence, urogenital system, Kidney metabolism, Nephrons, Sequence Analysis, DNA, medicine.disease, Kidney/metabolism, Endocrinology, Ion homeostasis, biology.protein, Carrier Proteins
Abstract: Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.
Published: 2012
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25. Role of research institutions in management of scientific fraud: The example of Inserm Scientific Integrity delegation

Author: Bungener, Martine, Hadchouel, M, CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), and Inserm-Délégation à l'intégrité scientifique
Subjects: [SHS]Humanities and Social Sciences
Abstract: International audience; Key points Fraud is only a part of misconduct in research. Very few French research Institutions have a scientific integrity office, and their prevention. The Institut national de la santé et de la recherche médicale (Inserm) has created a “Scientific Integrity delegation”. Scientific Integrity is an international concern. Scientific Integrity is closely linked to organisation, management and evaluation of all research activities. Points essentiels La fraude s’inscrit dans un continuum de mauvaises pratiques scientifiques qui relèvent de l’intégrité. Peu d’institutions de recherche françaises se sont dotées d’une structure spécifiquement dédiée à répondre aux manquements à l’intégrité scientifique et leur prévention. Nous abordons les principes de fonctionnement de la délégation à l’intégrité scientifique qui a été créé par l’ Institut national de la santé et de la recherche médicale (Inserm). L’intégrité scientifique devient une préoccupation internationale. L’intégrité scientifique a à voir avec l’organisation, la gestion et l’évaluation de l’activité de recherche.
Published: 2012
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26. WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice

Author: Sonia Bergaya, Xavier Jeunemaitre, Juliette Hadchouel, Gervaise Loirand, Marc Rio, Jean-Michel Achard, Brigitte Escoubet, Daniel Henrion, Sébastien Faure, Véronique Baudrie, Philippe Bonnin, Département de physiologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Architecture, Ville, Urbanisme, Environnement (LAVUE), École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Ministère de la Culture (MC)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Nanterre (UPN)-Ministère de la Culture (MC)-Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Nanterre (UPN)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Angers, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Architecture, Ville, Urbanisme, Environnement ( LAVUE ), Université Paris 8 Vincennes-Saint-Denis ( UP8 ) -Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), and Hôpital Européen Georges Pompidou [APHP] ( HEGP )
Subjects: Male, MESH: Phenylephrine, MESH : Carotid Arteries, Blood Pressure, MESH : Blotting, Western, MESH : Mice, 129 Strain, Mice, Phenylephrine, MESH : Phosphorylation, 0302 clinical medicine, MESH: Animals, 0303 health sciences, MESH : Vasoconstrictor Agents, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Blood Pressure, MESH : Norepinephrine, MESH: Vasoconstriction, MESH: Haploinsufficiency, MESH : Vasoconstriction, MESH : Haploinsufficiency, medicine.medical_specialty, MESH: Aorta, Thoracic, Blotting, Western, MESH : Solute Carrier Family 12, Member 2, MESH: Protein-Serine-Threonine Kinases, MESH : Angiotensin II, 03 medical and health sciences, MESH: Mice, 129 Strain, MESH: Blotting, Western, Dose-Response Relationship, Drug, MESH: Phosphorylation, MESH: Sodium-Potassium-Chloride Symporters, medicine.disease, Mice, Inbred C57BL, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, Endocrinology, Blood pressure, Vasoconstriction, MESH: Adrenergic alpha-1 Receptor Agonists, MESH: Female, MESH: Receptors, Adrenergic, alpha-1, Aorta, Thoracic, MESH : Dose-Response Relationship, Drug, Haploinsufficiency, 030204 cardiovascular system & hematology, Essential hypertension, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, Norepinephrine, WNK Lysine-Deficient Protein Kinase 1, MESH: Reverse Transcriptase Polymerase Chain Reaction, Solute Carrier Family 12, Member 2, Vasoconstrictor Agents, MESH : Female, Phosphorylation, Receptor, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Reabsorption, Angiotensin II, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Carotid Arteries, Female, MESH: Solute Carrier Family 12, Member 2, MESH: Angiotensin II, medicine.symptom, Signal transduction, MESH : Sodium-Potassium-Chloride Symporters, MESH : Adrenergic alpha-1 Receptor Agonists, MESH : Protein-Serine-Threonine Kinases, Mice, 129 Strain, MESH : Receptors, Adrenergic, alpha-1, Sodium-Potassium-Chloride Symporters, MESH : Male, Myogenic contraction, MESH : Mice, Inbred C57BL, In Vitro Techniques, Protein Serine-Threonine Kinases, Biology, Minor Histocompatibility Antigens, MESH: Vasoconstrictor Agents, MESH: Mice, Inbred C57BL, Receptors, Adrenergic, alpha-1, Internal medicine, MESH: Norepinephrine, MESH : Mice, MESH : Blood Pressure, Internal Medicine, medicine, Animals, MESH: Mice, MESH : Aorta, Thoracic, 030304 developmental biology, MESH: Carotid Arteries, MESH: Male, MESH : Phenylephrine, MESH : Mice, Knockout, Adrenergic alpha-1 Receptor Agonists, MESH : Animals, Ex vivo
Abstract: Gain-of-function mutations in the human WNK1 ( with-no-lysine[K]1 ) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1 +/− haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1 +/− mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α 1 -adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1 +/− arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na + -K + -2Cl − cotransporter 1) in Wnk1 +/− arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α 1 -adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α 1 -adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.
Published: 2011
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27. Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development

Author: Isabelle Halphen, Marie-Laure Franco-Montoya, Pierre-Henri Jarreau, Claude Danan, Fabrice Decobert, Jacques R. Bourbon, Emmanuel Martin, Alice Hadchouel, Olivier Boucherat, Serge Amselem, Alexandra Benachi, Christophe Delacourt, Institut Mondor de recherche biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Service de réanimation néonatale Port-Royal, CHU Cochin [AP-HP], Service de médecine néonatale de Port-Royal, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), IntegraGen, Service d'Obstétrique et Gynécologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Bases moléculaires et cellulaires des maladies génétiques, Unité Fonctionnelle de Recherche Clinique, CHI Créteil, Faculté de Médecine, IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], 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 Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges
Subjects: Male, MMP2, MESH : Polymorphism, Genetic, MESH : Prospective Studies, lcsh:Medicine, MESH: Rats, Sprague-Dawley, Matrix metalloproteinase, Rats, Sprague-Dawley, 0302 clinical medicine, MESH: Matrix Metalloproteinase 16, MESH: Animals, MESH : Female, Prospective Studies, lcsh:Science, Lung, MESH: Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia, 0303 health sciences, Multidisciplinary, MESH : Gene Expression Regulation, MESH : Rats, MESH: Infant, Newborn, MESH: Surface-Active Agents, Gestational age, respiratory system, Respiratory Medicine/Respiratory Pediatrics, MESH: Gene Expression Regulation, Trachea, medicine.anatomical_structure, MESH : Infant, Premature, MMP14, Female, MMP16, Infant, Premature, Research Article, MESH: Infant, Premature, MESH : Bronchopulmonary Dysplasia, MESH: Rats, MESH : Trachea, MESH : Lung, MESH : Male, Single-nucleotide polymorphism, Biology, MESH : Infant, Newborn, Andrology, Surface-Active Agents, 03 medical and health sciences, 030225 pediatrics, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Polymorphism, Genetic, MESH: Humans, lcsh:R, MESH : Humans, Infant, Newborn, MESH : Matrix Metalloproteinase 16, Matrix Metalloproteinase 16, medicine.disease, MESH: Prospective Studies, MESH: Male, MESH : Rats, Sprague-Dawley, Rats, Gene Expression Regulation, Bronchopulmonary dysplasia, Immunology, lcsh:Q, MESH : Surface-Active Agents, Pediatrics and Child Health/Neonatology, MESH : Animals, MESH: Female, MESH: Trachea, Developmental Biology
Abstract: International audience; BACKGOUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of
Published: 2008
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28. In vivo imaging of transplanted hepatocytes with a 1.5-T clinical MRI system--initial experience in mice

Author: Claire Wilhelm, Michèle Hadchouel, Gustavo Braga, Dominique Franco, Florence Gazeau, Lyes Boudechiche, Ibrahim Dagher, Alain Rahmouni, Olivier Clément, P. Smirnov, Anne Weber, Alexandre Parouchev, Aurore L’Hermine-Coulomb, Alain Luciani, Service d'imagerie médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Méthodes d'imagerie des échanges transcapillaires (LRI), IFR94-Université Paris Descartes - Paris 5 (UPD5), Transfert des gènes dans le foie : Applications thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM), Matière et Systèmes Complexes (MSC (UMR_7057)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie digestive et viscérale [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contrat GIS maladies rares, 2005/2006., Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Garcia, Marie, Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IFR94 - Université Paris Descartes - Paris 5 (UPD5), Matière et Systèmes Complexes (MSC), Université Paris Diderot - Paris 7 (UPD7) - Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Antoine Béclère
Subjects: Pathology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, medicine.medical_treatment, Contrast Media, Liver transplantation, Ferric Compounds, 1.5T, 030218 nuclear medicine & medical imaging, MESH: Magnetic Resonance Imaging, Cell therapy, MESH: Hepatocytes, chemistry.chemical_compound, Mice, 0302 clinical medicine, Image Processing, Computer-Assisted, MESH: Animals, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, 0303 health sciences, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], General Medicine, Magnetic Resonance Imaging, MESH: Image Processing, Computer-Assisted, MESH: Staining and Labeling, MESH: Cell Survival, Syngenic, MESH: Ferric Compounds, Preclinical imaging, Iron oxide nanoparticles, medicine.medical_specialty, Cell Survival, transplanted hepatocytes, Article, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Analysis of Variance, MESH: Contrast Media, In vivo, medicine, Animals, Radiology, Nuclear Medicine and imaging, Viability assay, [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], MESH: Mice, 030304 developmental biology, Analysis of Variance, mouse hepatocytes, Staining and Labeling, business.industry, [PHYS.MECA.BIOM] Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], In vitro, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Transplantation, Mice, Inbred C57BL, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, chemistry, clinical MRI System, Hepatocytes, Feasibility Studies, Nanoparticles, business, MESH: Feasibility Studies, MESH: Nanoparticles
Abstract: International audience; The feasibility of in vitro mature mouse hepatocyte labeling with a novel iron oxide particle was assessed and the ability of 1.5-T magnetic resonance imaging (MRI) to track labeled mouse hepatocytes in syngenic recipient livers following intraportal cell transplantation was tested. Mouse hepatocytes were incubated with anionic iron oxide nanoparticles at various iron concentrations. Cell viability was assessed and iron oxide particle uptake quantified. Labeled hepatocytes were intraportally injected into 20 mice, while unlabeled hepatocytes were injected into two mice. Liver T2 values, spleen-to-muscle relative signal intensity (RI( spleen/muscle )), and liver-to-muscle relative signal intensity (RI( liver/muscle )) on gradient-echo T2-weighted imaging after injection of either labeled or unlabeled hepatocytes were compared with an ANOVA test followed by Fisher's a posteriori PLSD test. Livers, spleens and lungs were collected for histological analysis. Iron oxide particle uptake was saturable with a maximum iron content of 20 pg per cell and without viability alteration after 3 days of culture. Following labeled-cell transplantation, recipient livers showed well-defined nodular foci of low signal intensity on MRI--consistent with clusters of labeled hepatocytes on pathological analysis--combined with a significant decrease in both liver T2 values and liver-to-muscle RI( liver/muscle ) (P = 0.01) with minimal T2 values demonstrated 8 days after transplantation. Conventional MRI can demonstrate the presence of transplanted iron-labeled mature hepatocytes in mouse liver.
Published: 2008
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29. Alagille syndrome in adult patients: it is never too late

Author: Jean-Pierre Grünfeld, Laure-Hélène Noël, Anne Guiochon-Mantel, Antoine Jacquet, Fadi Fakhouri, Tarik Sqalli, Pierre Bedossa, Michelle Hadchouel, Garcia, Marie, Service de néphrologie pédiatrique [CHU 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), Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Mecanismes de l'Inflammation et de l'Adherence Cellulaire Dans les Maladies Renales, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Transfert des gènes dans le foie : Applications thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP] - Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris-Sud - Paris 11 (UP11) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bicêtre, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Diderot - Paris 7 (UPD7) - Hôpital Beaujon, and Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bicêtre
Subjects: Nephrology, Adult, medicine.medical_specialty, Pathology, Time Factors, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, 030232 urology & nephrology, Disease, MESH : Kidney Failure, Chronic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Alagille syndrome, medicine, OMIM : Online Mendelian Inheritance in Man, Humans, MESH : Female, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, 030304 developmental biology, 0303 health sciences, MESH: Alagille Syndrome, MESH: Humans, Adult patients, business.industry, Vascular disease, MESH : Humans, MESH: Time Factors, MESH: Adult, MESH : Adult, medicine.disease, 3. Good health, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Interlobular bile ducts, Alagille Syndrome, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, MESH: Kidney Failure, Chronic, Kidney Failure, Chronic, Female, business, MESH : Alagille Syndrome, MESH: Female, Kidney disease, MESH : Time Factors
Abstract: International audience; Alagille syndrome (AGS; Online Mendelian Inheritance in Man no. 118450) is a multisystem autosomal dominant disorder with highly variable expression characterized by chronic cholestasis caused by a paucity of interlobular bile ducts, skeletal abnormalities, peculiar facies, ocular abnormalities, and cardiovascular disorders. AGS is diagnosed almost exclusively in children in the setting of predominant liver manifestations or, more rarely, in their adult relatives. We report 2 patients in whom AGS was diagnosed in adulthood during the workup of renal disease in the absence of a well-defined familial history. Renal disease caused by AGS probably is underdiagnosed in adult patients.
Published: 2007
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30. [Human embryonic stem cells to rescue fulminant hepatic failure]

Author: Herpe, Yves-Edouard, Hadchouel, Michelle, Weber, Anne, Thiéry, Jean-Paul, Laâbi, Yacine, Transfert de gènes dans le foie : applications thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), and Garcia, Marie
Subjects: MESH: Cell Culture Techniques, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, MESH: Humans, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Liver Failure, Acute, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, MESH: Embryonic Stem Cells, ComputingMilieux_MISCELLANEOUS, [SDV.BIO] Life Sciences [q-bio]/Biotechnology
Abstract: International audience
Published: 2006

31. Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries

Author: Damien Bonnet, Nigel A. Brown, Margaret Buckingham, Stéphane Zaffran, Fanny Bajolle, Juliette Hadchouel, Robert G. Kelly, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Heart Defects, Congenital, Rotation, Physiology, Persistent truncus arteriosus, Mice, Transgenic, 030204 cardiovascular system & hematology, Biology, Polymerase Chain Reaction, 03 medical and health sciences, Mice, 0302 clinical medicine, Double outlet right ventricle, medicine, Animals, Humans, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Aorta, 030304 developmental biology, DNA Primers, 0303 health sciences, Cardiac neural crest cells, Neural crest, Heart, Anatomy, Transposition of the great vessels, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Great arteries, Circulatory system, Myogenic Regulatory Factor 5, Cardiology and Cardiovascular Medicine, Artery
Abstract: Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch ( Pax3 ) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2δc mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2δc mutants, which have transposition of the great arteries. Because Pitx2c is involved in left–right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.
Published: 2006

32. Expression of mutant JAGGED1 alleles in patients with Alagille syndrome

Author: Nicole Raynaud, Catherine Driancourt, Michelle Hadchouel, Michèle Meunier-Rotival, Julie Boyer, Cécile Crosnier, Marie Gonzales, Transfert des gènes dans le foie : Applications thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hépato-gastro-entérologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Garcia, Marie
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Mutant, MESH: Calcium-Binding Proteins, MESH: Base Sequence, medicine.disease_cause, 0302 clinical medicine, Chlorocebus aethiops, Gene expression, Missense mutation, Serrate-Jagged Proteins, MESH: Animals, Lymphocytes, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Alagille Syndrome, MESH: COS Cells, COS Cells, Intercellular Signaling Peptides and Proteins, MESH: Membrane Proteins, Haploinsufficiency, JAG1, MESH: Mutation, Molecular Sequence Data, Biology, Transfection, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, MESH: Intercellular Signaling Peptides and Proteins, Alleles, 030304 developmental biology, MESH: Alagille Syndrome, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, MESH: Alleles, MESH: Transfection, Calcium-Binding Proteins, Membrane Proteins, Molecular biology, MESH: Cercopithecus aethiops, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, MESH: Cell Line, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, Membrane protein, Jagged-1 Protein, MESH: Lymphocytes, 030217 neurology & neurosurgery
Abstract: International audience; Heterozygous mutations in JAGGED1 (JAG1), encoding a ligand for Notch receptors, have been identified in patients with Alagille syndrome (AGS). These mutations map to the extracellular and transmembrane domains of JAG1, giving rise in 70% cases to a premature termination codon (PTC). Although haploinsufficiency has been hypothesised as the main mechanism of AGS, a dominant negative effect of truncated forms of Serrate/Jagged has been suggested. Only few studies of the mutant mRNAs and proteins from AGS patients have been performed to elucidate the molecular mechanisms of the disease. To gain insight into the stability of mutant mRNAs, we studied transcripts from five livers and 24 lymphoblastoid cell lines (LCLs) of AGS patients. Mutant JAG1 transcripts were recovered (albeit in different relative amounts) from RNAs with missense mutations (five) or in-frame deletions (two), and from all but two of the 21 with PTCs. In addition, results from LCL RNAs correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of a 23-week-old AGS foetus with a PTC mutation. This suggests that most mutant transcripts with PTCs escape nonsense-mediated mRNA decay (NMD) and could lead to the synthesis of soluble forms of JAG1. Production of a truncated protein was indeed observed after transfection of COS cells with a mutant JAG1 cDNA. In conclusion, mutant JAG1 transcripts are present in LCLs, livers and tissues of AGS patients, whatever the mutation type, and mutant proteins can be produced, suggesting a dominant negative effect of some mutant proteins as another molecular mechanism of AGS.
Published: 2005
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33. The formation of skeletal muscle: from somite to limb

Author: Frédéric Relaix, Margaret Buckingham, Didier Montarras, Lola Bajard, Philippe Daubas, Ted Hung-Tse Chang, Didier Rocancourt, Sigolène M. Meilhac, Juliette Hadchouel, Département de Biologie du Développement, Institut Pasteur [Paris], University of Edinburgh, M.B.'s laboratory is supported by the Pasteur Institute and the CNRS and by grants from the AFM, ARC, the ACI Integrative Biology programme of the French Ministry of Research and Technology (MRT) and the EU Biotechnology programme, grant no. QLK3-CT-1999-00020. T.C. holds an NIH postdoctoral fellowship. J.H. was supported by fellowships from the MRT and AFM. S.M. has also been supported by a fellowship from the MRT., and Institut Pasteur [Paris] (IP)
Subjects: MESH: Embryonic Induction, Gene Expression, MyoD, muscle progenitor cells, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, Morphogenesis, Myocyte, MESH: Animals, MESH: Vertebrates, Embryonic Induction, 0303 health sciences, muscle regeneration, MESH: Muscle, Skeletal, Myogenesis, Stem Cells, MESH: Regeneration, Gene Expression Regulation, Developmental, MESH: Myogenic Regulatory Factors, regulatory genes, vertebrate limb, musculoskeletal system, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, Myogenic Regulatory Factors, Vertebrates, Pax genes, MYF5, myogenesis, Anatomy, myogenic factors, medicine.medical_specialty, Histology, MESH: Gene Expression, Limb Buds, Reviews, MESH: Stem Cells, Biology, 03 medical and health sciences, Limb bud, Internal medicine, medicine, Animals, Regeneration, Muscle, Skeletal, Molecular Biology, MESH: Mice, Ecology, Evolution, Behavior and Systematics, Myogenin, 030304 developmental biology, MESH: Limb Buds, Skeletal muscle, Extremities, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Cell Biology, MESH: Morphogenesis, Somite, Endocrinology, MESH: Extremities, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Developmental Biology
Abstract: International audience; During embryogenesis, skeletal muscle forms in the vertebrate limb from progenitor cells originating in the somites. These cells delaminate from the hypaxial edge of the dorsal part of the somite, the dermomyotome, and migrate into the limb bud, where they proliferate, express myogenic determination factors and subsequently differentiate into skeletal muscle. A number of regulatory factors involved in these different steps have been identified. These include Pax3 with its target c-met, Lbx1 and Mox2 as well as the myogenic determination factors Myf5 and MyoD and factors required for differentiation such as Myogenin, Mrf4 and Mef2 isoforms. Mutants for genes such as Lbx1 and Mox2, expressed uniformly in limb muscle progenitors, reveal unexpected differences between fore and hind limb muscles, also indicated by the differential expression of Tbx genes. As development proceeds, a secondary wave of myogenesis takes place, and, postnatally, satellite cells become located under the basal lamina of adult muscle fibres. Satellite cells are thought to be the progenitor cells for adult muscle regeneration, during which similar genes to those which regulate myogenesis in the embryo also play a role. In particular, Pax3 as well as its orthologue Pax7 are important. The origin of secondary/fetal myoblasts and of adult satellite cells is unclear, as is the relation of the latter to so-called SP or stem cell populations, or indeed to potential mesangioblast progenitors, present in blood vessels. The oligoclonal origin of postnatal muscles points to a small number of founder cells, whether or not these have additional origins to the progenitor cells of the somite which form the first skeletal muscles, as discussed here for the embryonic limb.
Published: 2003
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34. Construction of an integrated physical and gene map of human chromosome 20p12 providing candidate genes for Alagille syndrome

Author: Michèle Meunier-Rotival, Claire Boccaccio, Sophie Dhorne-Pollet, Nicolas Pollet, Charles Auffray, Michelle Hadchouel, Nicole Raynaud, Catherine Driancourt, UPR 420, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), IDM Laboratoire Universitaire de Transfert en Immunologie (Luti) (IDM - LUTI), Université Pierre et Marie Curie - Paris 6 (UPMC)-IDM (Immuno-Designed Molecules), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Transfert des gènes dans le foie : Applications thérapeutiques, Service d'hépato-gastro-entérologie pédiatrique, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre
Subjects: Genetic Markers, Candidate gene, DNA, Complementary, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Restriction Mapping, Chromosomes, Human, Pair 20, Locus (genetics), Biology, localization, 03 medical and health sciences, Gene mapping, Complementary DNA, Alagille syndrome, human genome, Genetics, medicine, Humans, molecular analysis, Chromosomes, Artificial, Yeast, Gene, cdna, Sequence Tagged Sites, 030304 developmental biology, 0303 health sciences, Base Sequence, Gene map, 030305 genetics & heredity, Chromosome Mapping, sequence, medicine.disease, Alagille Syndrome, assignment, Genetic marker
Abstract: International audience; Physical mapping and localization of eSTS markers were used to generate an integrated physical and gene map covering a approximately 10-Mb region of human chromosome 20p12 containing the Alagille syndrome (AGS) locus. Seventy-four STSs, 28 of which were derived from cDNA sequences, mapped with an average resolution of 135 kb. The 28 eSTS markers define 20 genes. Six known genes, namely CHGB, BMP2, PLCB1, PLCB4, SNAP, and HJ1, were precisely mapped. Among the genes identified, one maps in the smallest region of overlap of the deletions associated with AGS and could therefore be regarded as a candidate gene for Alagille syndrome.
Published: 1997
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35. Construction of a 3.7-Mb physical map within human chromosome 20p12 ordering 18 markers in the alagille syndrome locus

Author: Nicole Raynaud, Catherine Driancourt, Sophie Dhorne-Pollet, Claire Boccaccio, D. Le Paslier, Michèle Meunier-Rotival, Nicolas Pollet, Jean-Francois Deleuze, Michelle Hadchouel, Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sanofi-Aventis, IDM Laboratoire Universitaire de Transfert en Immunologie (Luti) (IDM - LUTI), Université Pierre et Marie Curie - Paris 6 (UPMC)-IDM (Immuno-Designed Molecules), Transfert des gènes dans le foie : Applications thérapeutiques, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Service d'hépato-gastro-entérologie pédiatrique, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre
Subjects: Genetic Markers, Candidate gene, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Restriction Mapping, Chromosomes, Human, Pair 20, Locus (genetics), arteriohepatic dysplasia, Biology, dna, 03 medical and health sciences, Restriction map, clones, Gene mapping, Alagille syndrome, human genome, Genetics, medicine, Humans, deletion, Cloning, Molecular, Chromosomes, Artificial, Yeast, In Situ Hybridization, Fluorescence, DNA Primers, Sequence Tagged Sites, 030304 developmental biology, dinucleotide repeat polymorphism, 0303 health sciences, Base Sequence, Contig, 030305 genetics & heredity, Chromosome Mapping, Chromosome, library, sequence, medicine.disease, Alagille Syndrome, Chromosome Band, yeast artificial chromosomes, CpG Islands, linkage
Abstract: International audience; Alagille syndrome (AGS, MIM 118450) is associated with human chromosome band 20p12. To study this region, we constructed a 3.7-Mb physical map using 36 YACs isolated from the CEPH YAC library with three sequence-tagged sites (STS): D20S503, D20S41, and D20S188. New STSs were obtained from 6 isolated YAC end-fragments. Eighteen markers were ordered on the contig as follows:20ptel-D20S177-D20S175-D20S509- D20S5/D20S503-D20S506-D20S162-D20S504- D20S505-D20S507-D20S188-(D20S6-D20S27- D20S189)-D20S186-D20S41-D20S61-D20S492- D20S508-20pcen. A restriction map with the enzymes AscI, MluI, NotI, SacII, and SfiI was generated, revealing seven putative CpG islands. We established a YAC contig that spans the AGS region and thus will be valuable for cloning candidate genes and searching for DNA polymorphisms segregating with this syndrome.
Published: 1995
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36. [Alagille syndrome in 1995. Clinical and genetic data]

Author: Deleuze, J F, Dhorne-Pollet, Sophie, Pollet, N, Meunier-Rotival, M, Hadchouel, M, and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], hepatic ductular hypoplasia, chromosome 20, short arm, hepatocellular-carcinoma, [SDV]Life Sciences [q-bio], insitu hybridization, interlobular bile-ducts, submicroscopic deletions, syndrome arteriohepatic dysplasia, linkage map, ComputingMilieux_MISCELLANEOUS, contiguous gene syndromes
Abstract: National audience
Published: 1995

37. Le syndrome d'Alagille en 1995. Données cliniques et génétiques

Author: J F, Deleuze, S, Dhorne-Pollet, N, Pollet, M, Meunier-Rotival, M, Hadchouel, ProdInra, Migration, INSERM-TRANSFERT [Paris] (IT), Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Développement et évolution (DE), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: hepatocellular-carcinoma, [SDV]Life Sciences [q-bio], Chromosomes, Human, Pair 20, Chromosome Disorders, submicroscopic deletions, syndrome arteriohepatic dysplasia, MESH: Chromosomes, Human, Pair 20, Humans, MESH: Chromosome Aberrations, MESH: Radiography, ComputingMilieux_MISCELLANEOUS, Chromosome Aberrations, MESH: Chromosome Disorders, MESH: Alagille Syndrome, MESH: Humans, insitu hybridization, interlobular bile-ducts, linkage map, Alagille Syndrome, Radiography, [SDV] Life Sciences [q-bio], hepatic ductular hypoplasia, chromosome 20, MESH: Gene Deletion, short arm, Gene Deletion, contiguous gene syndromes
Abstract: International audience
Published: 1995

38. Segregation analysis of Alagille syndrome

Author: Sophie Dhorne-Pollet, M Hadchouel, C Bonaïti-Pellié, Jean-Francois Deleuze, Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Biologie François JACOB (JACOB), 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), Transfert des gènes dans le foie : Applications thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Epidémiologie génétique
Subjects: Male, Proband, Genotype, Genetic counseling, butterfly vertebra, [SDV]Life Sciences [q-bio], Chromosomes, Human, Pair 20, Gene Expression, Disease, arteriohepatic dysplasia, Biology, 03 medical and health sciences, 0302 clinical medicine, Alagille syndrome, Genetics, medicine, Humans, Expressivity (genetics), deletion, Child, Genetics (clinical), Genes, Dominant, Probability, 030304 developmental biology, 0303 health sciences, Models, Genetic, Genetic disorder, medicine.disease, Penetrance, Pedigree, Alagille Syndrome, Phenotype, Genetic Techniques, Female, 030211 gastroenterology & hepatology, Research Article, contiguous gene syndromes
Abstract: International audience; Alagille syndrome (AGS) is a well defined genetic disorder characterised by five major features. An autosomal dominant mode of transmission with reduced penetrance has been suggested by the analysis of a limited number of families. However there has been no statistical analysis. We report here the first segregation analysis of AGS, using 33 families collected through 43 probands. Segregation analysis of these families allowed us to conclude that AGS is transmitted as a dominant disorder with 94% penetrance and 15% of cases are sporadic. The expressivity of the phenotype was variable and 26 persons (15 parents and 11 sibs) were identified as presenting minor forms of the disease. These results are valuable for genetic counselling.
Published: 1994
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39. Deleted chromosome 20 from a patient with alagille syndrome isolated in a cell hybrid through leucine transport selection: study of three candidate genes

Author: Nicolas Pollet, Nicole Raynaud, Jamilé Hazan, Michèle Meunier-Rotival, Michelle Hadchouel, S. Dhorne, Jean-Francois Deleuze, Daniel Alagille, Jean Deschatrette, E. Borghi, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de Biologie François JACOB (JACOB), 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), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Structure et évolution des génomes (SEG), CNS-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie maxillo-faciale, stomatologie et odontologie hospitalière [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Développement et évolution (DE), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Molecular Neuroimaging
Subjects: clone (Java method), Candidate gene, deaminase, [SDV]Life Sciences [q-bio], Chromosomes, Human, Pair 20, CHO Cells, Biology, Hybrid Cells, cell Hybrid, prion Protein, 03 medical and health sciences, 0302 clinical medicine, Cricetulus, Leucine, Cricetinae, Centromere, Alagille syndrome, Genetics, medicine, Animals, Humans, Paired Box Transcription Factors, Lymphocytes, Cystatin C, Selection, Genetic, In Situ Hybridization, Fluorescence, 030304 developmental biology, 0303 health sciences, Leucine transport, Chromosome, Nuclear Proteins, somatic cell hybrid, medicine.disease, Molecular biology, Cystatins, Alagille Syndrome, DNA-Binding Proteins, Genes, adenosine, 030220 oncology & carcinogenesis, Hepatocyte Nuclear Factor 3-beta, Leucine-tRNA Ligase, hybrid clone, Restriction fragment length polymorphism, Chromosome 20, Chromosome Deletion, Transcription Factors
Abstract: International audience; Alagille syndrome (AGS) is a well-defined genetic entity assigned to the short arm of Chromosome (Chr) 20 by a series of observations of AGS patients associated with microdeletions in this region. By fusing lymphoblastoid cells of an AGS patient that exhibited a microdeletion in the short arm of Chr 20 encompassing bands p11.23 to p12.3 with rodent thermosensitive mutant cells (CHOtsH1-1) deficient in-leucyl-tRNA synthetase, we isolated a somatic cell hybrid segregating the deleted human Chr 20. This hybrid clone, designated NR2, was characterized by several methods, including PCR, with eight pairs of oligonucleotides mapped to Chr 20: D20S5, D20S41, D20S42, D20S56, D20S57, D20S58, adenosine deaminase (ADA), and Prion protein (PRIP); Restriction Fragment Length Polymorphism (RFLP) analyses with four genomic anonymous probes (D20S5, cD3H12, D20S17, D20S18); and fluorescent in situ hybridization (FISH) with total human DNA and D20Z1, a sequence specific to the human Chr 20 centromere, as probes. The NR2 hybrid allowed us to exclude three candidate genes for AGS: hepatic nuclear factor 3 beta (HNF3 beta), paired box 1 (PAX1), and cystatin C (CST3) as shown by their localization outside of the deletion. The NR2 hybrid is a powerful tool for the mapping of new probes of this region, as well as for obtaining new informative probes specific for the deletion by subtractive cloning of the region. Such markers will be useful for linkage analysis and screening of cDNA libraries.
Published: 1994
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40. Mapping of microsatellite markers in the alagille region and screening of microdeletions by genotyping 23 patients

Author: Jean-Francois Deleuze, Jamilé Hazan, Sophie Dhorne, Jean Weissenbach, Michelle Hadchouel, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-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)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay
Subjects: Genetic Markers, Male, Genotype, [SDV]Life Sciences [q-bio], Chromosomes, Human, Pair 20, Locus (genetics), Biology, DNA, Satellite, 03 medical and health sciences, region flanked, 0302 clinical medicine, 030225 pediatrics, Alagille syndrome, Genetics, medicine, alagille syndrome, Humans, Typing, Genotyping, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Chromosome Mapping, microsatellite markers, medicine.disease, Pedigree, Genetic marker, Microsatellite, Female, Chromosome 20, Gene Deletion
Abstract: International audience; Alagille syndrome (AGS) has been assigned to 20p11.23-20p12.2 according to minimum overlap between deletions observed on the chromosome 20 short arm of 9 patients. We report here the localisation of 5 microsatellite markers (D20S41, D20S48, D20S50, D20S56, and D20S58) within the deletion of one AGS patient. This study allows an estimation of the genetic extent of this deletion as being between 30 and 36 cM, and demonstrates its paternal origin. The search for submicroscopic deletions in 23 AGS patients, by typing these 5 markers, failed to reveal allelic loss. However, these results lead to the proposition that the AGS locus lies in one of the seven intervals defined by the six microsatellite markers in the region flanked by D20S5 and D20S18.
Published: 1994
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41. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases

Author: Francois Potet, Christian Bréchot, Jacques Scotto, Girish N. Vyas, Michelle Hadchouel, Pierre Tiollais, Michelle Fonck, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bicêtre, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California [San Francisco] (UC San Francisco), University of California (UC), This work was supported by grants from the Institut National de la Sante et de la Recherche Medicale, the Foundation pour la Recherche Medicale, and the University of Paris VII. G.N.V. was a Fulbright Scholar on sabbatical leave at the Institut Pasteur, Paris., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: Hepatitis B virus, Carcinoma, Hepatocellular, Hepatitis B virus DNA polymerase, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, Hepatitis B virus PRE beta, MESH: Nucleic Acid Hybridization, 03 medical and health sciences, 0302 clinical medicine, MESH: Liver Neoplasms, medicine, Humans, MESH: Carcinoma, Hepatocellular, 030304 developmental biology, Southern blot, Hepatitis, 0303 health sciences, Multidisciplinary, Hepatitis B Surface Antigens, MESH: Humans, MESH: Hepatitis B, Liver Neoplasms, Nucleic Acid Hybridization, virus diseases, Hepatitis B, medicine.disease, Virology, digestive system diseases, 3. Good health, MESH: DNA, Viral, MESH: Hepatitis B Surface Antigens, MESH: Hepatitis B virus, HBeAg, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Immunology, DNA, Viral, Research Article, MESH: Liver
Abstract: International audience; Using the Southern blot technique and cloned hepatitis B virus (HBV) DNA as a probe, we studied the state of HBV DNA in the liver of 13 patients with hepatocellular carcinoma, 17 patients with chronic hepatitis, and 2 patients with acute hepatitis. The hybridization results were compared with the serological and immunohistological data. Integration of HBV DNA in cellular DNA of the liver from patients with hepatocellular carcinoma was demonstrated. In two patients from which tumorous and nontumorous liver tissue samples were available the integration patterns were different. In one patient with hepatitis B e antigen (HBeAg)-positive early hepatocellular carcinoma, free viral DNA was present in the liver. In some patients with HBeAg-negative chronic hepatitis, without tumor, integration of HBV DNA in cellular DNA was also demonstrated. This suggests that HBV is not the only factor involved in the development of a tumor. In patients with HBeAg-positive chronic hepatitis, free viral DNA was detected in the liver. In the two acute hepatitis patients analyzed, the restriction endonuclease patterns strongly suggested HBV DNA integration. Therefore, viral DNA integration seems to occur early in infection. Whatever the form of the disease, discrete bands were observed, suggesting the existence of limited and specific integration sites in host cellular DNA. The presence of integrated or free DNA sequences has implications for antiviral therapy. In addition, detection of HBV DNA in the liver is another sensitive viral marker that could be useful for diagnostic purposes.
Published: 1981
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42. The Role of Connexin 43 in Renal Disease: Insights from In Vivo Models of Experimental Nephropathy

Author: Elena Roger, Louis Boutin, Christos E. Chadjichristos, Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée (CoRaKID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Hadchouel, Juliette
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, kidney disease, Organic Chemistry, General Medicine, Kidney, Fibrosis, Connexins, Catalysis, animal models, Computer Science Applications, connexin 43, Inorganic Chemistry, Animals, Humans, experimental nephropathy, Renal Insufficiency, Chronic, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Renal disease is a major public health challenge since its prevalence has continuously increased over the last decades. At the end stage, extrarenal replacement therapy and transplantation remain the only treatments currently available. To understand how the disease progresses, further knowledge of its pathophysiology is needed. For this purpose, experimental models, using mainly rodents, have been developed to unravel the mechanisms involved in the initiation and progression of renal disease, as well as to identify potential targets for therapy. The gap junction protein connexin 43 has recently been identified as a novel player in the development of kidney disease. Its expression has been found to be altered in many types of human renal pathologies, as well as in different animal models, contributing to the activation of inflammatory and fibrotic processes that lead to renal damage. Furthermore, Cx43 genetic, pharmacogenetic, or pharmacological inhibition preserved renal function and structure. This review summarizes the existing advances on the role of this protein in renal diseases, based mainly on different in vivo animal models of acute and chronic renal diseases.
Published: 2022
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43. Toward a better comprehension of WNK1, Cullin-3 and SPAK implication in familial hyperkalemic hypertension

Author: Rafael, Chloé, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité, and Juliette Hadchouel
Subjects: NCC, Kinases WNK, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, urogenital system, E3 ubiquitine ligase, Hypertension, SPAK, Ubiquitine ligase E3, WNK kinases, Distal nephron, Néphron distal
Abstract: Familial Hyperkalemic Hypertension (FHHt) is a rare form of hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. These disorders are all corrected by thiazide diuretics that inhibit the Na+-Cl- NCC cotransporter expressed in the distal nephron. The sensitivity of FHHt patients to thiazide diuretics strongly suggested that FHHt is caused by NCC activation. In 2001, gain-of function-mutations were identified in the genes encoding the serine-threonine kinases WNK1 and WNK4 [With No (K) lysine] in a subst of FHHt patients. In vitro studies demonstrate that WNK1 and WNK4 indirectly stimulate NCC, through the phosphorylation and activation of SPAK (Ste20 like Proline-Alanine rich Kinase). In vivo, SPAK activation plays a central role in the pathogenesis of FHHt caused by WNK4 mutations. However, the implication of SPAK has never been shown for the WNK1 mutations. Thus, we crossed WNK1+/FHHt mice, bearing the WNK1-FHHt mutation, with SPAK243A/243A mice bearing a mutation abolishing SPAK activation by the WNKs. All FHHt phenotypes observed in WNK1+/FHHt were corrected in WNK1+/FHHt:SPAK243A/243A mice demonstrating the central role of SPAK in FHHt caused by WNK1 mutations. In 2012, new mutations have been identified in CUL3 and KLHL3 genes. The products of these genes are both part of a ubiquitin ligase complex. As WNK1 and WNK4 mutations, these mutations lead to an increased expression of L-WNK1 and/or WNK4. Surprisingly, patients with CUL3 mutations display a more severe phenotype. Previous studies have suggested that CUL3 could be involved not only in the regulation of ion transport in the distal nephron but also in the regulation of vascular tone. To verify this hypothesis, we generated and compared two mouse models: pgk-Cul3Δ9 mouse model bearing, as patients, an ubiquitous Cul3 mutation, and sm22-Cul3Δ9 mouse model that express the Cul3 mutation only in vascular smooth muscle cells. Both models are hypertensive, but pgk-Cul3Δ9 mice display a more severe hypertension than sm22-Cul3Δ9 mice. It demonstrates that the hypertension caused by Cul3 mutations results from both renal and vascular disorders. Recently, new missense mutations have been identified in WNK1 acidic motif in a small number of FHHt patients. This acidic motif is necessary for the liaison to KLHL3 and therefore for WNK ubiquitination. Our study shows that, in vitro, these mutations lead to the accumulation of only one isoform of WNK1. In mice, the mutation of WNK1 acidic motif leads to an increased phosphorylation of SPAK and NCC. Therefore, it demonstrates the essential role of the acidic motif in the regulation of WNK1 abundance in vivo in the distal nephron. This work contributes to a better comprehension of the role played by SPAK, WNK1 and CUL3 in FHHt and more generally in the regulation of blood pressure and Na+/K+ homeostasis.; L’Hypertension Hyperkaliémique Familiale (FHHt) est une forme rare d’hypertension artérielle associée à une hyperkaliémie et une acidose métabolique hyperchlorémique. Ces troubles sont corrigés par les diurétiques thiazidiques qui inhibent le co-transporteur Na+-Cl- NCC exprimé dans le néphron distal. Cette sensibilité aux diurétiques thiazidiques a laissé́ supposer que la FHHt est causée par une activation de NCC. En 2001, des mutations, de type gain-de-fonction, responsables de la FHHt ont été découvertes dans les gènes codant les sérine-thréonine kinases WNK1 et WNK4 [With No (K) lysine]. Des études in vitro ont montré que WNK1 et WNK4 stimulent NCC de façon indirecte, via la phosphorylation et l'activation de la kinase SPAK (Ste20 like Proline-Alanine rich Kinase). In vivo, l’activation de SPAK joue un rôle central dans le développement de la FHHt due aux mutations de WNK4. L'implication de SPAK n'a pas été définie dans le cas des mutations de WNK1. Nous avons donc croisé les souris WNK1+/FHHt, porteuses d'une mutation FHHt de WNK1, avec les souris SPAK243A/243A, porteuses d’une mutation abolissant l’activation de SPAK par les WNK. L’ensemble des phénotypes observés chez les souris WNK1+/FHHt est corrigé chez les souris WNK1+/FHHt:SPAK243A/243A démontrant ainsi le rôle central de SPAK dans la FHHt causée par les mutations WNK1. En 2012, de nouvelles mutations ont été identifiées dans les gènes codant CUL3 et KLHL3, deux composants d’un complexe ubiquitine ligase. Comme les mutations de WNK1 et WNK4, ces mutations entraînent une augmentation de l’expression de WNK1 et de WNK4. De façon inattendue, les patients FHHt porteurs d'une mutation CUL3 présentent un phénotype plus sévère que les autres. Des études suggèrent que ces mutations perturbent la fonction non seulement du néphron distal mais également des artères. Afin de vérifier cette hypothèse, nous avons généré et comparé deux modèles de souris : les souris pgk-Cul3Δ9, exprimant la mutation Cul3 de façon ubiquitaire, comme les patients, et les souris sm22-Cul3Δ9, exprimant la mutation uniquement dans les cellules musculaires vasculaires lisses. Les deux modèles sont hypertendus, mais les souris pgk-Cul3Δ9 le sont significativement plus que les souris sm22-Cul3Δ9, ce qui prouve que l’hypertension causée par les mutations Cul3 résulte du cumul d’une atteinte rénale et vasculaire. Récemment, de nouvelles mutations faux-sens d'un domaine dit acide de WNK1 ont été identifiées dans un petit nombre de patients atteints de FHHt. Ce domaine est nécessaire à la liaison à KLHL3 et donc à l’ubiquitination des WNK. Notre étude montre que, in vitro, ces mutations entraînent une accumulation d'une seule isoforme de WNK1. Chez la souris, la mutation du domaine acide provoque le même phénotype que les patients, ainsi qu’une augmentation de la phosphorylation de SPAK et du co-transporteur NCC. Cette étude a donc permis de démontrer le rôle essentiel de ce domaine dans la régulation de l'abondance de WNK1 dans le néphron distal in vivo. En conclusion, mon travail a permis une meilleure compréhension du rôle joué par SPAK, WNK1 et CUL3 dans le développement de la FHHt et, plus largement, de la physiopathologie de la FHHt.
Published: 2017

44. Toward a better comprehension of WNK1, Cullin-3 and SPAK implication in familial hyperkalemic hypertension

Author: Rafael, Chloé, STAR, ABES, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité, and Juliette Hadchouel
Subjects: NCC, Kinases WNK, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, urogenital system, E3 ubiquitine ligase, Hypertension, SPAK, Ubiquitine ligase E3, WNK kinases, Distal nephron, Néphron distal, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Familial Hyperkalemic Hypertension (FHHt) is a rare form of hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. These disorders are all corrected by thiazide diuretics that inhibit the Na+-Cl- NCC cotransporter expressed in the distal nephron. The sensitivity of FHHt patients to thiazide diuretics strongly suggested that FHHt is caused by NCC activation. In 2001, gain-of function-mutations were identified in the genes encoding the serine-threonine kinases WNK1 and WNK4 [With No (K) lysine] in a subst of FHHt patients. In vitro studies demonstrate that WNK1 and WNK4 indirectly stimulate NCC, through the phosphorylation and activation of SPAK (Ste20 like Proline-Alanine rich Kinase). In vivo, SPAK activation plays a central role in the pathogenesis of FHHt caused by WNK4 mutations. However, the implication of SPAK has never been shown for the WNK1 mutations. Thus, we crossed WNK1+/FHHt mice, bearing the WNK1-FHHt mutation, with SPAK243A/243A mice bearing a mutation abolishing SPAK activation by the WNKs. All FHHt phenotypes observed in WNK1+/FHHt were corrected in WNK1+/FHHt:SPAK243A/243A mice demonstrating the central role of SPAK in FHHt caused by WNK1 mutations. In 2012, new mutations have been identified in CUL3 and KLHL3 genes. The products of these genes are both part of a ubiquitin ligase complex. As WNK1 and WNK4 mutations, these mutations lead to an increased expression of L-WNK1 and/or WNK4. Surprisingly, patients with CUL3 mutations display a more severe phenotype. Previous studies have suggested that CUL3 could be involved not only in the regulation of ion transport in the distal nephron but also in the regulation of vascular tone. To verify this hypothesis, we generated and compared two mouse models: pgk-Cul3Δ9 mouse model bearing, as patients, an ubiquitous Cul3 mutation, and sm22-Cul3Δ9 mouse model that express the Cul3 mutation only in vascular smooth muscle cells. Both models are hypertensive, but pgk-Cul3Δ9 mice display a more severe hypertension than sm22-Cul3Δ9 mice. It demonstrates that the hypertension caused by Cul3 mutations results from both renal and vascular disorders. Recently, new missense mutations have been identified in WNK1 acidic motif in a small number of FHHt patients. This acidic motif is necessary for the liaison to KLHL3 and therefore for WNK ubiquitination. Our study shows that, in vitro, these mutations lead to the accumulation of only one isoform of WNK1. In mice, the mutation of WNK1 acidic motif leads to an increased phosphorylation of SPAK and NCC. Therefore, it demonstrates the essential role of the acidic motif in the regulation of WNK1 abundance in vivo in the distal nephron. This work contributes to a better comprehension of the role played by SPAK, WNK1 and CUL3 in FHHt and more generally in the regulation of blood pressure and Na+/K+ homeostasis., L’Hypertension Hyperkaliémique Familiale (FHHt) est une forme rare d’hypertension artérielle associée à une hyperkaliémie et une acidose métabolique hyperchlorémique. Ces troubles sont corrigés par les diurétiques thiazidiques qui inhibent le co-transporteur Na+-Cl- NCC exprimé dans le néphron distal. Cette sensibilité aux diurétiques thiazidiques a laissé́ supposer que la FHHt est causée par une activation de NCC. En 2001, des mutations, de type gain-de-fonction, responsables de la FHHt ont été découvertes dans les gènes codant les sérine-thréonine kinases WNK1 et WNK4 [With No (K) lysine]. Des études in vitro ont montré que WNK1 et WNK4 stimulent NCC de façon indirecte, via la phosphorylation et l'activation de la kinase SPAK (Ste20 like Proline-Alanine rich Kinase). In vivo, l’activation de SPAK joue un rôle central dans le développement de la FHHt due aux mutations de WNK4. L'implication de SPAK n'a pas été définie dans le cas des mutations de WNK1. Nous avons donc croisé les souris WNK1+/FHHt, porteuses d'une mutation FHHt de WNK1, avec les souris SPAK243A/243A, porteuses d’une mutation abolissant l’activation de SPAK par les WNK. L’ensemble des phénotypes observés chez les souris WNK1+/FHHt est corrigé chez les souris WNK1+/FHHt:SPAK243A/243A démontrant ainsi le rôle central de SPAK dans la FHHt causée par les mutations WNK1. En 2012, de nouvelles mutations ont été identifiées dans les gènes codant CUL3 et KLHL3, deux composants d’un complexe ubiquitine ligase. Comme les mutations de WNK1 et WNK4, ces mutations entraînent une augmentation de l’expression de WNK1 et de WNK4. De façon inattendue, les patients FHHt porteurs d'une mutation CUL3 présentent un phénotype plus sévère que les autres. Des études suggèrent que ces mutations perturbent la fonction non seulement du néphron distal mais également des artères. Afin de vérifier cette hypothèse, nous avons généré et comparé deux modèles de souris : les souris pgk-Cul3Δ9, exprimant la mutation Cul3 de façon ubiquitaire, comme les patients, et les souris sm22-Cul3Δ9, exprimant la mutation uniquement dans les cellules musculaires vasculaires lisses. Les deux modèles sont hypertendus, mais les souris pgk-Cul3Δ9 le sont significativement plus que les souris sm22-Cul3Δ9, ce qui prouve que l’hypertension causée par les mutations Cul3 résulte du cumul d’une atteinte rénale et vasculaire. Récemment, de nouvelles mutations faux-sens d'un domaine dit acide de WNK1 ont été identifiées dans un petit nombre de patients atteints de FHHt. Ce domaine est nécessaire à la liaison à KLHL3 et donc à l’ubiquitination des WNK. Notre étude montre que, in vitro, ces mutations entraînent une accumulation d'une seule isoforme de WNK1. Chez la souris, la mutation du domaine acide provoque le même phénotype que les patients, ainsi qu’une augmentation de la phosphorylation de SPAK et du co-transporteur NCC. Cette étude a donc permis de démontrer le rôle essentiel de ce domaine dans la régulation de l'abondance de WNK1 dans le néphron distal in vivo. En conclusion, mon travail a permis une meilleure compréhension du rôle joué par SPAK, WNK1 et CUL3 dans le développement de la FHHt et, plus largement, de la physiopathologie de la FHHt.
Published: 2017

45. The Murine Ortholog of Notchless, a Direct Regulator of the Notch Pathway in Drosophila melanogaster, Is Essential for Survival of Inner Cell Mass Cells

Author: Stéphanie Le Bras, Sandrine Vandormael-Pournin, Sarah Cormier, Celine Souilhol, Michel Cohen-Tannoudji, Béatrice Durand, Patricia Baldacci, Charles Babinet, Cohen-Tannoudji, Michel, Biologie du Développement, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus et Transfert Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Association pour la Recherche contre le Cancer (ARC), the Institut Pasteur GPH07 on stem cells, and the Action concertée incitative Biologie du Développement et Physiologie Intégrative from the Ministère de l'Education Nationale, de la Recherche, et de la Technologie. S.C. received grants from the Pasteur-Negri-Weizmann Council and the ARC. S.L.B. received funding from the Ministere de l'Education Nationale and was a recipient of funding from the ARC. C.S. received grants from CNRS (Bourse de Doctorat pour les Ingénieurs)., We thank J. Artus, S. Tajbakhsh, J. Hadchouel, F. Relaix, and C. Brou for helpful discussions, C. Kress for her invaluable help and instruction with culture and manipulation of ES cells, and S. Lecorre for technical help. We acknowledge the dynamic imaging platform, Institut Pasteur, for helpful assistance., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Embryo, Nonmammalian, MESH: Mice, Mutant Strains, Xenopus, Regulator, Apoptosis, MESH: Amino Acid Sequence, Mice, MESH: Embryo Implantation, 0302 clinical medicine, Inner cell mass, MESH: Animals, MESH: Xenopus, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Caspase, 0303 health sciences, Receptors, Notch, biology, Articles, Cell biology, Drosophila melanogaster, Notch proteins, embryonic structures, Female, MESH: Membrane Proteins, Molecular Sequence Data, Notch signaling pathway, Cell fate determination, MESH: Drosophila melanogaster, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Animals, Cell Lineage, Amino Acid Sequence, Embryo Implantation, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Apoptosis, MESH: Embryo, Mammalian, Membrane Proteins, MESH: Embryo, Nonmammalian, Cell Biology, MESH: Cell Lineage, Embryo, Mammalian, biology.organism_classification, Embryonic stem cell, Mice, Mutant Strains, MESH: Male, biology.protein, Genes, Lethal, MESH: Genes, Lethal, MESH: Receptors, Notch, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Notch signaling is an evolutionarily conserved pathway involved in intercellular communication and is essential for proper cell fate choices. Numerous genes participate in the modulation of the Notch signaling pathway activity. Among them, Notchless (Nle) is a direct regulator of the Notch activity identified in Drosophila melanogaster. Here, we characterized the murine ortholog of Nle and demonstrated that it has conserved the ability to modulate Notch signaling. We also generated mice deficient for mouse Nle (mNle) and showed that its disruption resulted in embryonic lethality shortly after implantation. In late mNle(-/-) blastocysts, inner cell mass (ICM) cells died through a caspase 3-dependent apoptotic process. Most deficient embryos exhibited a delay in the temporal down-regulation of Oct4 expression in the trophectoderm (TE). However, mNle-deficient TE was able to induce decidual swelling in vivo and properly differentiated in vitro. Hence, our results indicate that mNle is mainly required in ICM cells, being instrumental for their survival, and raise the possibility that the death of mNle-deficient embryos might result from abnormal Notch signaling during the first steps of development.
Published: 2006
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46. Genetic study of alagille syndrome and physical mapping of a corresponding locus in 20p12

Author: Dhorne-Pollet, Sophie, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6, Michelle Hadchouel, and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], these
Abstract: Le syndrome d'alagille (ags, mim 118450) est un syndrome malformatif complexe caracterise par l'association de cinq elements majeurs: une paucite des canaux biliaires interlobulaires, une stenose peripherique des branches de l'artere pulmonaire, des vertebres dites en ailes de papillon, un embryotoxon posterieur et un facies particulier. Une analyse de segregation nous a permis de confirmer le mode de transmission autosomique dominant de l'ags. Pour la premiere fois la penetrance et la proportion de cas sporadiques ont ete estimees respectivement a 94% et 15%. L'observation de deletions du bras court du chromosome 20 associees au syndrome d'alagille a oriente nos recherches au niveau de la bande 20p12. Afin de pouvoir tester l'implication de genes candidats, leur localisation par rapport a une deletion mise en evidence chez un patient ags, a ete etudiee. Ce chromosome 20 delete a ete isole dans un hybride somatique homme-hamster. Le gene pax1 candidat a l'apparition des anomalies vertebrales, le gene hnf3b candidat a la paucite ductulaire et le gene cst3 responsable d'hemorragies intracraniennes ont ete etudies. L'implication de ces trois genes a ete rejetee par la demonstration de leur localisation a l'exterieur de la deletion. Afin de mettre en place les outils indispensables au clonage du ou des genes impliques dans l'ags, une cartographie physique a l'aide de chromosomes artificiels de levure a ete mise en uvre. Une carte physique de 3,7 mb composee de 37 yac, ordonnant 29 marqueurs a ete construite. La zdc apparait avoir une taille de 2,2 mb. Une analyse de liaison genetique devait permettre de preciser la localisation moleculaire du syndrome d'alagille. Les resultats nous amene a exclure le locus ags d'une region de plus de 35 cm qui s'etend de d20s175 a d20s48 et qui englobe completement la zdc. De plus, cette analyse a permis de localiser de facon distale a l'haplotype d20s5-d20s162 (z=3,21 ; =0,05) un locus implique dans le syndrome d'alagille. Ces resultats nous amenent a proposer qu'un effet de position pourrait etre le mecanisme sous-jacent responsable du phenotype atteint chez les patients presentant une deletion n'impliquant pas le locus ags.
Published: 1996

47. Etude génétique du syndrome d'alagille et cartographie physique d'un locus correspondant en 20p12

Author: Dhorne-Pollet, Sophie, ProdInra, Migration, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6, and Michelle Hadchouel
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], these
Abstract: Le syndrome d'alagille (ags, mim 118450) est un syndrome malformatif complexe caracterise par l'association de cinq elements majeurs: une paucite des canaux biliaires interlobulaires, une stenose peripherique des branches de l'artere pulmonaire, des vertebres dites en ailes de papillon, un embryotoxon posterieur et un facies particulier. Une analyse de segregation nous a permis de confirmer le mode de transmission autosomique dominant de l'ags. Pour la premiere fois la penetrance et la proportion de cas sporadiques ont ete estimees respectivement a 94% et 15%. L'observation de deletions du bras court du chromosome 20 associees au syndrome d'alagille a oriente nos recherches au niveau de la bande 20p12. Afin de pouvoir tester l'implication de genes candidats, leur localisation par rapport a une deletion mise en evidence chez un patient ags, a ete etudiee. Ce chromosome 20 delete a ete isole dans un hybride somatique homme-hamster. Le gene pax1 candidat a l'apparition des anomalies vertebrales, le gene hnf3b candidat a la paucite ductulaire et le gene cst3 responsable d'hemorragies intracraniennes ont ete etudies. L'implication de ces trois genes a ete rejetee par la demonstration de leur localisation a l'exterieur de la deletion. Afin de mettre en place les outils indispensables au clonage du ou des genes impliques dans l'ags, une cartographie physique a l'aide de chromosomes artificiels de levure a ete mise en uvre. Une carte physique de 3,7 mb composee de 37 yac, ordonnant 29 marqueurs a ete construite. La zdc apparait avoir une taille de 2,2 mb. Une analyse de liaison genetique devait permettre de preciser la localisation moleculaire du syndrome d'alagille. Les resultats nous amene a exclure le locus ags d'une region de plus de 35 cm qui s'etend de d20s175 a d20s48 et qui englobe completement la zdc. De plus, cette analyse a permis de localiser de facon distale a l'haplotype d20s5-d20s162 (z=3,21 ; =0,05) un locus implique dans le syndrome d'alagille. Ces resultats nous amenent a proposer qu'un effet de position pourrait etre le mecanisme sous-jacent responsable du phenotype atteint chez les patients presentant une deletion n'impliquant pas le locus ags.
Published: 1996

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