176 results on '"Caroline Kannengiesser"'
Search Results
52. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi–Hünermann–Happle Syndrome
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Stéphane Bézieau, Sandra Mercier, Thomas Besnard, Mathilde Nizon, Mathilde Pacault, Norbert Winer, Smail Hadj-Rabia, Stéphanie Leclerc-Mercier, Madeleine Joubert, Sébastien Barbarot, Khaldia Belabbas, Claire Beneteau, Marie Vincent, Caroline Kannengiesser, Antonin Lamaziere, Fabienne Dufernez, Xenia Latypova, Bertrand Isidor, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Hopital Xavier Bichat, Partenaires INRAE, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomo-pathologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique, and Centre hospitalier universitaire de Poitiers (CHU Poitiers)
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Adult ,Male ,0301 basic medicine ,Chondrodysplasia Punctata ,RNA Splicing ,Steroid Isomerases ,medicine.disease_cause ,Short stature ,Article ,X-inactivation ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Chondrodysplasia punctata ,Genetics (clinical) ,Mutation ,Ichthyosis ,business.industry ,Alternative splicing ,Intron ,syndrome ,medicine.disease ,Pedigree ,Phenotype ,030104 developmental biology ,Aborted Fetus ,Female ,medicine.symptom ,Klinefelter syndrome ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.
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- 2018
53. Un score prédictif de la survenue de pneumopathie interstitielle diffuse préclinique au cours de la polyarthrite rhumatoïde
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Arnaud Constantin, Olivier Vittecoq, Francis Berenbaum, F. Louis-Sidney, A. Saraux, Marie-Pierre Debray, J. Sibilia, Caroline Kannengiesser, R.M. Flipo, Xavier Mariette, Raphael Borie, B. Combe, P.A. Juge, Esther Ebstein, Bruno Fautrel, Catherine Boileau, G. Carvajal Alegria, Bruno Crestani, Joanna Kedra, Benjamin Granger, and Philippe Dieudé
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Rheumatology - Published
- 2021
54. TERT promoter mutations and liver carcinogenesis: identification and quantification of mutation status by digital PCR analysis on formol-fixed paraffin-embedded samples
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Sarah, Paisley, primary, Ibrahima, Ba, additional, Aurélie, Beaufrère, additional, Albuquerque, Miguel, additional, Soubrane, Olivier, additional, Caroline, Kannengiesser, additional, and Paradis, Valérie, additional
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- 2020
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55. Liver involvement in patients with telomere-related genes mutations: prevalence, clinical, radiological, pathological features, outcome and risk factors
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Sidali, Sabrina, primary, Borie, Raphaël, additional, Flore, Sicre, additional, Lainey, Elodie, additional, Rautou, Pierre-Emmanuel, additional, Cadranel, Jacques, additional, Naccache, Jean-marc, additional, Cottin, Vincent, additional, Dumortier, Jérôme, additional, Jacquemin, Emmanuel, additional, Baptiste, Nousbaum Jean, additional, Hirschi, Sandrine, additional, Bourdin, Arnaud, additional, Meszaros, Magdalena, additional, Dharancy, Sebastien, additional, Hilaire, Sophie, additional, Mallet, Vincent, additional, Martine, Reynaud-Gaubert, additional, Terriou, Louis, additional, Gottrand, Frédéric, additional, Chahla, Wadih Abou, additional, Khan, Jean Emmanuel, additional, Carrier, Paul, additional, Saliba, Faouzi, additional, Rubbia-Brandt, Laura, additional, Elkrief, Laure, additional, de Lédinghen, Victor, additional, Abergel, Armand, additional, Olivier, Tournilhac, additional, Chouik, Yasmina, additional, Coupier, Antoine, additional, Leblanc, Thierry, additional, Ollivier-Hourmand, Isabelle, additional, Khac, Eric Nguyen, additional, Morisse-Pradier, Hélène, additional, El Husseini, Kinan, additional, Goria, Odile, additional, Ibrahima, Ba, additional, Roulot, Dominique, additional, Bureau, Christophe, additional, Nunes, Hilario, additional, Valla, Dominique, additional, Paradis, Valérie, additional, Caroline, Kannengiesser, additional, and Plessier, Aurélie, additional
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- 2020
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56. Pneumopathies interstitielles diffuses associées aux mutations de Poly(A)-specific ribonuclease (PARN) : une étude de cohorte rétrospective multicentrique
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Martine Reynaud-Gaubert, Hilario Nunes, Raphael Borie, Bruno Crestani, Q. Philippot, D. Israel Biet, Frédéric Schlemmer, Effrosyni D. Manali, Hervé Mal, Vincent Cottin, Benjamin Bondue, Spyros Papiris, Anne Gondouin, Caroline Kannengiesser, Jean-Marc Naccache, and Lidwine Wemeau
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Pulmonary and Respiratory Medicine - Abstract
Introduction Des mutations de Poly(A)-specific ribonuclease (PARN) ont ete associees a des cas familiaux de fibrose pulmonaire. Le phenotype des patients presentant une pneumopathie interstitielle diffuse (PID) et une mutation de PARN est cependant mal decrit. Methodes Nous avons realise une etude retrospective, observationnelle, non interventionnelle. Tous les patients avec une PID et une mutation de PARN, suivis dans les centres du reseau OrphaLung, ont ete inclus. Resultats Vingt patients, issus de 12 familles, ont ete inclus. L’âge median lors du diagnostic de PID etait de 58,8 ans (ecart interquartile [IQR] de 52,8 a 64,5 ans). Les diagnostics les plus frequents etaient : fibrose pulmonaire idiopathique (FPI ; n = 8 ; 40 %) et fibrose inclassable (n = 5 ; 12,5 %). L’hemogramme, disponible pour 17 patients, et le bilan hepatique, disponible pour 16 patients, etaient normaux. Treize patients ont recu un traitement specifique pour leur PID comme suit : corticoides (n = 8), anti-fibrosant (n = 6), immunosuppresseur (n = 2) et N-acetyl-cysteine (n = 1). Sept patients n’ont pas recu de traitement specifique. Aucun patient n’a presente une amelioration respiratoire (objectivee par des epreuves fonctionnelles respiratoires ou une diminution des besoins en oxygene). Le declin median de capacite vitale forcee, pour l’ensemble de la population, etait de 219 mL par an (IQR de −73 a −511). Apres un suivi median de 2,9 ans (IQR de 0,93 a 7,1), sept patients sont decedes et cinq patients ont ete transplantes. Conclusion Cette etude objective que les mutations de PARN sont le plus souvent associees avec une FPI, d’autres phenotypes peuvent neanmoins etre observes. Une telle heterogeneite phenotypique implique une evaluation complete des PID associees aux mutations de PARN afin de definir une strategie therapeutique adaptee.
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- 2020
57. Impact clinique de la mutation BRAFV600E dans l’histiocytose Langerhansienne pulmonaire de l’adulte
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Shannon Cohen, D. Gossot, Emmanuelle Clappier, Céleste Lebbé, Fanélie Jouenne, Alain Haziot, G. Lorillon, Véronique Meignin, Emmanuelle Bugnet, Aurélie Sadoux, Caroline Kannengiesser, Sylvie Chevret, Abdellatif Tazi, Alexandre How-Kit, and Samia Mourah
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,03 medical and health sciences ,0302 clinical medicine ,030105 genetics & heredity ,030217 neurology & neurosurgery - Abstract
Introduction Plusieurs groupes, dont le notre, ont identifie la mutation BRAF V600E, activatrice de la voie des mitogen activated protein kinases (MAPK), dans les lesions d’histiocytose Langerhansienne pulmonaire (HLP), mais sa signification clinique n’a pas ete etudiee. Afin d’evaluer son impact clinique dans l’HLP de l’adulte, nous avons genotype un nombre important de lesions provenant des patients suivis au centre de reference des histiocytoses et recherche une association entre la presence de la mutation BRAF V600E et leurs caracteristiques au diagnostic et au cours du suivi. Methodes La recherche de la mutation BRAF V600E a ete realisee par des techniques de biologie moleculaire dans 83 biopsies provenant de patients adultes atteints d’HLP (43 hommes, âge median 36 ans, 65 fumeurs et 16 ex-fumeurs, atteinte pulmonaire isolee n = 51). Les caracteristiques des patients ont ete extraites de la base de donnees prospective du registre des histiocytoses. Au cours du suivi, l’aggravation de l’atteinte pulmonaire etait definie par l’alteration de la fonction respiratoire et/ou la survenue d’un pneumothorax [1] . La probabilite d’aggravation au cours du suivi a ete estimee par la methode de Kaplan–Meier. Des modeles de Cox ont ete utilises pour tester l’association entre les caracteristiques des patients au diagnostic et le risque de progression ulterieure de l’atteinte pulmonaire. Resultats Une mutation BRAF V600E a ete detectee dans 31 (37 %) lesions. Il n’y avait pas de difference dans la presentation initiale de l’HLP selon le statut BRAF, en particulier pour le tabagisme (p = 0,42), la survenue d’un pneumothorax (p = 0,29), ou la fonction respiratoire (p > 0,05 pour tous les parametres fonctionnels). Les patients ont ete suivis pendant une duree mediane de 5 ans. Trente-huit (46 %) patients ont presente une progression de leur atteinte pulmonaire. L’incidence cumulee d’aggravation de l’HLP au cours de l’evolution etait similaire que les lesions soient mutees BRAF V600E ou non (p = 0,99) ( Fig. 1 ). Dans cette serie de patients, la presence d’un trouble ventilatoire obstructif au diagnostic etait associee a un risque accru de progression de l’atteinte pulmonaire, y compris en analyse multivariee (p = 0,025). Conclusion Dans cette cohorte importante de patients adultes ayant une HLP, la mutation BRAF V600E n’etait pas associee a une presentation particuliere de la maladie et ne modifiait pas le risque de progression de l’atteinte pulmonaire au cours de l’evolution.
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- 2020
58. The
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Mark G J P, Platenburg, Ivo A, Wiertz, Joanne J, van der Vis, Bruno, Crestani, Raphael, Borie, Philippe, Dieude, Caroline, Kannengiesser, Jacobus A, Burgers, Jan C, Grutters, and Coline H M, van Moorsel
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Asbestosis ,Humans ,Promoter Regions, Genetic ,Mucin-5B ,Alleles ,Idiopathic Pulmonary Fibrosis - Published
- 2019
59. Somatic genetic rescue in Mendelian haematopoietic diseases
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Alain Fischer, Patrick Revy, Caroline Kannengiesser, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
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MESH: Mutation ,Somatic cell ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Biology ,MESH: Phenotype ,MESH: Microcephaly ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Germline mutation ,Neoplasms ,Genetics ,Animals ,Humans ,MESH: Animals ,MESH: Neoplasms ,Molecular Biology ,Genetics (clinical) ,Genetic mosaicism ,030304 developmental biology ,MESH: Symptom Flare Up ,0303 health sciences ,MESH: Humans ,Mosaicism ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,MESH: Multiprotein Complexes ,MESH: Hematologic Diseases ,MESH: RNA, Transfer ,Hematologic Diseases ,Phenotype ,3. Good health ,Haematopoiesis ,On cells ,MESH: RNA-Binding Proteins ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Mutation ,MESH: Nephrosis ,Mendelian inheritance ,symbols ,MESH: Mosaicism ,Cancer development ,MESH: Nuclear Proteins ,030217 neurology & neurosurgery - Abstract
International audience; Somatic mutations occur spontaneously in normal individuals and accumulate throughout life. These genetic modifications contribute to progressive ageing phenotypes and are directly involved in cancer development. However, a growing number of studies of Mendelian haematopoietic disorders indicate that somatic genetic events can offset the pathogenic effect of germline mutations at the cellular level, leading to genetic mosaicism and, in some cases, resulting in a milder disease phenotype. Notably, spontaneous genetic events that confer a positive effect on cells do not always benefit the individual, for whom the effects can be neutral or even clinically detrimental. These somatic genetic rescue events have important diagnostic, therapeutic and clinical consequences and constitute valuable models for studying the differentiation and/or homeostasis of haematopoietic lineages.
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- 2019
60. Clinical outcomes after lung transplantation for fibrosis in telomerase related genes mutation carriers
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Stéphane Jouneau, Sylvain Marchand Adam, Hilario Nunes, Jean-Marc Naccache, Jérôme Le Pavec, Martine Reynaud-Gaubert, Antoine Froidure, Aurélie Le Borgne, Christophe Pison, Bruno Crestani, Lidwine Wemeau-Stervinou, Raphael Borie, François Philit, Antoine Roux, Sandrine Hirschi, Hervé Mal, Vincent Cottin, Romain Lazor, Caroline Kannengiesser, Mathilde Phillips Houlbracq, Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de pneumologie (Strasbourg), CHU Strasbourg-Nouvel Hôpital Civil, Service de pneumologie. Centre de compétence des maladies pulmonaires rares, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de chirurgie thoracique et transplantation pulmonaire, Centre chirurgical Marie Lannelongue, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [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), Contaminants Chimiques, immunité et Inflammation, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Hôpital Nord [CHU - 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), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Centre Chirurgical Marie Lannelongue (CCML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)
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medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,Idiopathic pulmonary fibrosis ,Neutropenia ,Gastroenterology ,Liver disease ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Median follow-up ,Internal medicine ,Pulmonary fibrosis ,medicine ,Transplantation pulmonaire ,Lung transplantation ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,Lung ,business.industry ,Fibrose pulmonaire ,medicine.disease ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,3. Good health ,medicine.anatomical_structure ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,business - Abstract
International audience; Carriers of telomerase related genes (TRG) mutation seem to present a worst prognosis with more common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT and identify pre-LT prognosis factors in a multicenter cohort of lung transplant recipients with TRG mutation.We retrospectively reviewed all identified patients with pathogenic TRG mutation (n=38; TERT, n=22, TERC, n=10, RTEL1, n=6) who received LT in France, Switzerland and Belgium between 2009 and 2018. The median age at LT was 54 years (46-59), 70% were male, and 60% had idiopathic pulmonary fibrosis (IPF). At diagnosis of pulmonary fibrosis, 84% had a hematological disease, including 8 with myelodysplasia, and 45% had a liver disease. After a median follow up of 2.2 years (1,2-3,7), 16 received a single LT, 22 a double LT and 2 a combined liver-LT.The overall post-LT median survival was 3.75 years (1.8-NA). Patients with myelodysplasia before LT had an increased risk of death after LT (HR= 4.12 (1.47-11.53) p=0.007). After LT, all patients showed anemia, 70% thrombocytopenia, and 60% neutropenia. Four patients showed severe liver disease: portal hypertension, cirrhosis. Sixteen patients (42%) experienced acute renal failure and 18 (47%) developed chronic renal insufficiency during follow up. Four developed chronic lung allograft dysfunction.Overall survival after LT supports LT in TRG mutation carriers. Careful evaluation at diagnosis, might limit LT indication for patients with established myelodysplasia.
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- 2019
61. Real-life experience of familial fibrosis in a Belgian university
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Anne De Leener, Caroline Kannengiesser, Caroline Dahlqvist, Anne-sophie Petit, Antoine Froidure, and Raphael Borie
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Genetic counseling ,Lung fibrosis ,Interstitial lung disease ,medicine.disease ,Pulmonary function testing ,Idiopathic pulmonary fibrosis ,Fibrosis ,Internal medicine ,Pulmonary fibrosis ,medicine ,business ,Genetic testing - Abstract
Introduction: Familial pulmonary fibrosis (FPF) is defined as lung fibrosis affecting at least 2 members of the 1st degree of a family. Monogenic pulmonary fibrosis is usually investigated in this case and/or when an idiopathic interstitial lung disease occurs in a patient younger than 55 years-old, eventually associated with extra-thoracic involvement. We reviewed all FPF cases seen in our university (2 tertiary hospitals) in 2017 and 2018. Methods: All FPF patients and an equal number of sporadic idiopathic pulmonary fibrosis (IPF) diagnosed between January 1st 2017 and December 31st 2018 were included in a database. Baseline characteristics, lung function tests, HRCT and histological patterns, haematological and liver features and one-year survival were studied. We used Mann-Whitney U and Chi-Square tests for statistical analysis. Our local ethics committee approved the study. Results: In 2017 and 2018, 24 patients had suspected FPF and/or monogenic lung fibrosis (3.9% of all patients discussed in multidisciplinary meeting). They were significantly younger (median age at diagnosis 63 ± 11 years) as compared to the 24 sporadic IPF patients (73 ± 9 years), P = 0.002. Fifteen FPF patients (62.5%) agreed to undergo genetic testing. We identified a mutation of the telomerase complex in 6 of them (40%). Extra-pulmonary involvement was significantly associated with FPF (P = 0.02). One-year mortality was significantly higher in FPF (29%) as compared to IPF (4%), P = 0.02. Conclusion: Our study confirms that FPF represents a substantial part of ILD, has a poor prognosis and is associated with extra-pulmonary involvement and younger age. Those patients require early support, multidisciplinary approach and genetic counselling.
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- 2019
62. Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison
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Panagiotis Tsirigotis, Catherine Boileau, Konstantinos Kagouridis, Demosthenes Bouros, Lykourgos Kolilekas, Patrick Revy, Paschalina Giouleka, Raphael Borie, Effrosyni D. Manali, Caroline Kannengiesser, Spyros Papiris, Vassiliki Pappa, Georgia Papadaki, Andriana I. Papaioannou, Bruno Crestani, Konstantinos Gkirkas, National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, 2nd Propedeutic Clinic of Internal Medicine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Second Department of Internal Medicine, Propaedeutic, University of Athens Medical School [Athens], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medical School, Democritus University of Thrace (DUTH), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), University of Athens, Medical School, University General Hospital Attikon, and Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
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Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Exacerbation ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,TINF2 ,medicine.disease_cause ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Pulmonary fibrosis ,medicine ,Humans ,Letter to the Editor ,Aged ,lcsh:RC705-779 ,Aged, 80 and over ,Mutation ,business.industry ,Myelodysplastic syndromes ,Bone marrow failure ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,lcsh:Diseases of the respiratory system ,Symptom Flare Up ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,3. Good health ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,030228 respiratory system ,Myelodysplastic Syndromes ,Female ,business - Abstract
International audience; Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients
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- 2019
63. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome
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Dana Ranta, Jean Donadieu, Pekka Jaako, Alan J. Warren, Etienne Lengliné, Laetitia Kermasson, Christine Bellanné-Chantelot, Angela Hoslin, Alexandre Faille, Hubert Ducou Le Pointe, Patrick Revy, Abraham Acevedo-Arozena, Christine Bole-Feysot, Caroline Kannengiesser, Blandine Beaupain, Shengjiang Tan, Patrick Nitschke, Odile Fenneteau, Jean-Pierre de Villartay, Stefano Fumagalli, Maryline Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Service d'hématologie-immunologie-oncologie pédiatrique [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), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National History Museum of London, Acevedo-Arozena, Abraham [0000-0001-6127-7116], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), 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)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Hémato-oncologie Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS)-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 Saint-Antoine [APHP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
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Male ,Models, Molecular ,Ribosomopathy ,Protein Conformation ,DNA Mutational Analysis ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,medicine.disease_cause ,Biochemistry ,Ribosome ,Mice ,0302 clinical medicine ,Peptide Initiation Factors ,Large ribosomal subunit ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,Genetics ,0303 health sciences ,Shwachman–Diamond syndrome ,Mutation ,Translation (biology) ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Hematology ,Shwachman-Diamond Syndrome ,3. Good health ,Pedigree ,Phenotype ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,EIF6 ,030220 oncology & carcinogenesis ,Female ,Disease Susceptibility ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Immunology ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Structure-Activity Relationship ,Red Cells, Iron, and Erythropoiesis ,medicine ,Animals ,Humans ,Ribonucleoprotein, U5 Small Nuclear ,030304 developmental biology ,Whole Genome Sequencing ,Infant ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,medicine.disease ,Peptide Elongation Factors ,Disease Models, Animal ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Ribosome Subunits ,Genome-Wide Association Study - Abstract
Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
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- 2019
64. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome
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Nicolas Pottier, Ibrahima Ba, Maname Benyelles, Emmanuelle Ollivier, Patrick Revy, Laetitia Kermasson, Elodie Lainey, Cécile Fourrage, Alicia Fernandes, Raphael Borie, Marie-Françoise O'Donohue, Caroline Kannengiesser, Chantal Lagresle-Peyrou, Hilario Nunes, Anne-Sophie Gamez, Bruno Crestani, Denis Caillaud, Fanny Morice-Picard, Jean-Pierre de Villartay, Isabelle Callebaut, Christelle Ménard, Clarisse Cazelles, Ambroise Marçais, Pierre-Emmanuel Gleizes, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), 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, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Pneumologie et Allergologie, CHU Clermont-Ferrand, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bichat - Claude Bernard, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure de Lyon (ENS de 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), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE11-0029,RIBOMAN,Une approche intégrative de la biogenèse des ribosomes(2016), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Impact de l'environnement chimique sur la santé humaine (IMPECS)
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0301 basic medicine ,Premature aging ,Male ,Telomerase ,Transcription, Genetic ,Pulmonary Fibrosis ,Sequence Homology ,Hoyeraal-Hreidarsson syndrome ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Biology ,medicine.disease_cause ,Dyskerin ,Dyskeratosis Congenita ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Intellectual Disability ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Promoter Regions, Genetic ,Molecular Biology ,Genetics (clinical) ,Aged ,Mutation ,Fetal Growth Retardation ,Infant, Newborn ,Nuclear Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Ribonucleoproteins, Small Nuclear ,3. Good health ,Telomere ,Pedigree ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,RNA, Ribosomal ,030220 oncology & carcinogenesis ,Cancer research ,Microcephaly ,Female ,Dyskeratosis congenita - Abstract
Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal–Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.
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- 2019
65. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis
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Pearce G. Wilcox, Joel M. Guthridge, Oliver Eickelberg, Mary E. Strek, Michael P. Keane, Yasunari Miyazaki, Doris Rassl, Osamu Narumoto, Moisés Selman, Jonathan A. Kropski, Maryl Kreider, Seamus C. Donnelly, Joao A. de Andrade, Geoffrey J. Laurent, Claudia Ravaglia, Michelle E. Armstong, Peter Saunders, Edwin K. Silverman, Yuben Moodley, Sydney B. Montesi, Tsukasa Okamoto, John S. Sundy, Tasha E. Fingerlin, Julie Powers, Jonathan Cardwell, Masaki Hirose, John Sembrat, Joyce S. Lee, Ho Cheol Kim, Yoshikazu Inoue, Karin A. Pacheco, David A. Schwartz, Tarik Walker, Ivana V. Yang, Camille M. Moore, Roberto Carbone, Martina Vasakova, Steven D. Nathan, Vivi Danchel, Michael Henry, Thomas G. O'Riordan, Helen Parfrey, Annie Pardo, Merte Lemma WoldeHanna, Nesrin Mogulkoc, Francesco Bonella, Philip L. Molyneaux, Alvaro Aranda, Martina Sterclova, Yingze Zhang, Ian Glaspole, Toby M. Maher, Barry S. Shea, Tejaswini Kulkarni, Peter Doran, Maria Molina-Molina, Namrata Patel, Haruhiko Furusawa, Dong Soon Kim, Kenneth B. Beckman, Svetlana Baltic, Feng Li, Drew C. Venuto, Harold R. Collard, Avram D Walts, Venerino Poletti, Shwu Fan Ma, Maho Suzukawa, Tracy Luckhardt, Nikhil Hirani, Wonjun Ji, Bruno Crestani, Kevin K. Brown, R. Gisli Jenkins, Caroline Kannengiesser, Christopher J. Ryerson, Aoife McElroy, Pamela Russell, Marvin I. Schwarz, Jin Woo Song, Ana Montes Worboys, Rachel Z. Blumhagen, Gauri Saini, Gunnar Gudmundsson, James D. Crapo, Paul J. Wolters, Sara Tomassetti, Christine A Fiddler, Lisa A. Maier, Carol Bair, Nurdan Kokturk, James E. Loyd, Rebecca Braybrooke, Shinobu Akagawa, Raphael Borie, Mauricio Rojas, Jürgen Behr, Tamera J. Corte, Michael H. Cho, Joy D. Cogan, Mark P. Steele, Susan K. Mathai, Francesco Puppo, Toru Arai, Kevin F. Gibson, Makenna Bishop, Isis E. Fernandez, Mary K. Porteous, Imre Noth, Jeffrey J. Swigris, Anna J. Podolanczuk, Brian Vestal, Cecilia M. Prêle, Ken Ohta, David J. Lederer, Deborah A. Nickerson, Elisabeth Bendstrup, Helgi J Isaksson, Cheryl Markin, Judith A. James, Carlos Machahua, Daniel J. Kass, Azin S. Poon, Ege Üniversitesi, National Institute for Health Research, and British Lung Foundation
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Male ,Genetic variants ,Respiratory System ,Cell ,Medizin ,LOCI ,Disease ,MUC5B PROMOTER POLYMORPHISM ,SUSCEPTIBILITY ,Critical Care and Intensive Care Medicine ,DISEASE ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,Promoter Regions, Genetic ,Telomerase ,Cellular Senescence ,11 Medical and Health Sciences ,Pulmonary Surfactant-Associated Protein A ,GTPase-Activating Proteins ,High-Throughput Nucleotide Sequencing ,ASSOCIATION ,Targeted resequencing ,respiratory system ,idiopathic pulmonary fibrosis ,Mucin-5B ,Pulmonary Surfactant-Associated Protein C ,GENOME ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Female ,DNA Sequence Analysis ,Life Sciences & Biomedicine ,Pulmonary and Respiratory Medicine ,Senescence ,EXPRESSION ,Telomere-Binding Proteins ,macromolecular substances ,03 medical and health sciences ,Critical Care Medicine ,General & Internal Medicine ,Humans ,disease risk alleles ,Genetic Predisposition to Disease ,Gene ,Science & Technology ,business.industry ,Host (biology) ,MUTATIONS ,genetic variants ,DNA Helicases ,Editorials ,Genetic Variation ,rare variants ,Rare variants ,Sequence Analysis, DNA ,targeted resequencing ,medicine.disease ,Logistic Models ,030228 respiratory system ,Case-Control Studies ,Exoribonucleases ,Immunology ,RNA ,ATP-Binding Cassette Transporters ,business ,Disease risk alleles ,Genome-Wide Association Study - Abstract
EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
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- 2019
66. Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes
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Louis Potier, Manuel Sanchez, Kamel Mohammedi, Michel Marre, Samy Hadjadj, Caroline Kannengiesser, Ronan Roussel, Gilberto Velho, and Sophie Hoang
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gastroenterology ,Amputation, Surgical ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Leukocytes ,Humans ,030212 general & internal medicine ,Advanced and Specialized Nursing ,Type 1 diabetes ,business.industry ,Incidence (epidemiology) ,Incidence ,Hazard ratio ,Absolute risk reduction ,Telomere Homeostasis ,Odds ratio ,DNA ,Middle Aged ,Telomere ,medicine.disease ,Diabetic Foot ,Diabetes Mellitus, Type 1 ,Lower Extremity ,Cohort ,Disease Progression ,Female ,business ,Reactive Oxygen Species ,Oxidation-Reduction ,Cohort study - Abstract
OBJECTIVE Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk. RESEARCH DESIGN AND METHODS LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3). RESULTS Among 478 participants (56% male, mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32–1.22] and for T3 vs. T1 0.41 [0.20–0.84]) but not with plasma 8-OHdG (1.16 [0.56–2.39] and 1.24 [0.61–2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08–0.67] and T3 vs. T1 0.29 [0.10–0.77]) and plasma 8-OHdG higher (2.20 [0.76–7.35] and 3.11 [1.07–10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA. CONCLUSIONS We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.
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- 2019
67. A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
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Gérard Friedlander, Ernesto Martín-Núñez, Víctor G. Tagua, Carol Prieto-Morín, Pablo Ureña-Torres, Caroline Kannengiesser, Claire Oudin, Javier Donate-Correa, David-Paul De Brauwere, Christine Leroy, and Juan F. Navarro-González
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Fibroblast growth factor 23 ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Article ,Klotho ,Frameshift mutation ,End stage renal disease ,fibroblast growth factor 23 ,03 medical and health sciences ,Exon ,Hyperphosphatemia ,0302 clinical medicine ,Medicine ,deletion ,hyperphosphatemia ,Gene ,030304 developmental biology ,0303 health sciences ,end-stage renal disease ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,Molecular biology ,haploinsufficiency ,business ,Haploinsufficiency - Abstract
Hyperphosphatemia is commonly present in end-stage renal disease. Klotho (KL) is implicated in phosphate homeostasis since it acts as obligate co-receptor for the fibroblast growth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variation in the KL gene might be associated with alterations in phosphate homeostasis resulting in hyperphosphatemia. We performed sequencing for determining KL gene variants in a group of resistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencing revealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation caused a frameshift with substitution of isoleucine for phenylalanine and introduction of a premature termination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carrier transcripts in peripheral blood mononuclear cells suggesting degradation of these through a nonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variant impaired FGF23 signaling pathway, indicating a functional inactivation of the gene. In the patient, serum levels of KL were 2.9-fold lower than the mean level of a group of matched dialysis subjects, suggesting a compromise in the circulating protein concentration due to haploinsufficiency. These findings provide a new loss-of-function variant in the human KL gene, suggesting that genetic determinants might be associated to clinical resistant hyperphosphatemia.
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- 2019
68. Regulator of telomere length 1 ( RTEL1 ) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes
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Arturo Londoño-Vallejo, Clément Gauvain, Julie Traclet, Tristan Dégot, Vincent Cottin, Marie Wislez, Raphael Borie, Bruno Crestani, Stéphane Dominique, Lidwine Wemeau-Stervinou, Patrick Revy, Aurélie Cazes, Caroline Kannengiesser, Pierre-Antoine Juge, Hilario Nunes, Christelle Ménard, Diane Bouvry, Catherine Boileau, Jacques Cadranel, Marie-Pierre Debray, Sébastien Quétant, Anne Sophie Gamez, Hervé Mal, Grégoire Prévot, Philippe Dieudé, Madeleine Jaillet, Arnaud Mailleux, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de Radiologie [Bichat] (DR- Bichat), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Service de Rhumatologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP, CHU Rouen, Normandie Université (NU), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), 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), Telomeres and Cancer Laboratory, Institut Curie, Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Service de cardiologie, Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey, Centre Hospitalier Universitaire [Grenoble] (CHU), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Université de Lyon-Université de Lyon, Service de pneumologie. Centre de compétence des maladies pulmonaires rares, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Theranoscan, Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre de Recherche Saint-Antoine (UMRS893), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Université Paris Diderot - Paris 7 (UPD7)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR SMBH-Université Paris 13 (UP13), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Gene mutation ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Fibrosis ,Pulmonary fibrosis ,Medicine ,Telomerase reverse transcriptase ,Exome ,Exome sequencing ,business.industry ,Interstitial lung disease ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,respiratory system ,medicine.disease ,3. Good health ,respiratory tract diseases ,030104 developmental biology ,030228 respiratory system ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,business - Abstract
Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.
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- 2019
69. Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry
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Nizar Mahlaoui, Capucine Picard, Perrine Bach, Laurence Costes, Virginie Courteille, Anja Ranohavimparany, Alexandre Alcaïs, Jean-Philippe Jais, Alain Fischer, Christine Bellanné-Chantelot, Jacinta Bustamante, Sylvie Chollet-Martin, Christian Drouet, Véronique Fremeaux-Bacchi, Caroline Kannengiesser, Virginie Girardin, Nathalie Lambert, Valérie Proulle, Jérémie Rosain, Marie José Stasia, Dominique Stoppa Lyonnet, Ioannis Theodorou, Wadih Abou-Chahla, Daniel Adoue, Nathalie Aladjidi, Zahir Amoura, Corinne Armari-Alla, Brigitte Bader-Meunier, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, Claire Briandet, Jean-Paul Brion, Jacques Brouard, Liana Carausu, Emilie Catherinot, Nathalie Cheikh, Sarah Cohen-Beaussant, Louis-Jean Couderc, Pierre Cougoul, Gérard Couillault, Geneviève de Saint Basile, Catherine Devoldere, Anne Deville, Eric Dore, Fabienne Dulieu, Isabelle Durieu, Natacha Entz Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, Catherine Gaud, Bernard Grosbois, Aurélien Guffroy, Corinne Guitton, Gaelle Guillerm, Eric Hachulla, Mohamed Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, Cyrille Hoarau, Bruno Hoen, Arnaud Hot, Sébastien Humbert, Arnaud Jaccard, Serge Jacquot, Rolland Jaussaud, Pierre-Yves Jeandel, Eric Jeziorski, Kamila Kebaili, Anne-Sophie Korganow, Olivier Lambotte, Fanny Lanternier, Claire Larroche, Alain Le Quellec, Emmanuelle Le Moigne, Vincent Le Moing, David Launay, Yvon Lebranchu, Marc Lecuit, Guillaume Lefevre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Marion Malphettes, Aude Marie-Cardine, Nicolas Martin Silva, Agathe Masseau, Christian Massot, Françoise Mazingue, Etienne Merlin, Gérard Michel, Frédéric Millot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Munzer, Bénédicte Neven, Raphaëlle Nove-Josserand, Dalila Nouar, Eric Oksenhendler, Marie Ouachée-Chardin, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Perel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Pierre Quartier, Frédéric Rieux-Laucat, Pascal Roblot, Pierre-Simon Rohrlich, Bruno Royer, Valéry Salle, Françoise Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stephan, Nicolas Schleinitz, Felipe Suarez, Laure Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, Caroline Thumerelle, Jean-Pierre Vannier, Jean-François Viallard, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Service de Biostatistique et Informatique Médicale, Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Immunologie 'Autoimmunité et Hypersensibilités' [AP-HP Hôpital Bichat, Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche et d'Etude du Processus Inflammatoire (GREPI), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'immunologie [HEGP, Paris], 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), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), the Study Center of Primary Immunodeficiencies, CHU Necker - Enfants Malades [AP-HP], Hémostase et biologie vasculaire, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Immunologie et de Maladies Infectieuses (CIMI), 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 Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital de la Tronche, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hématogoie pédiatrique, hôpital Sud, SIGNAL-IMAGE-COMMUNICATION (SIC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Pneumologie et Centre de Compétence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat, Paris], Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Pédiatrie Enfants - Hématologie Oncologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service des Maladies Infectieuses, CHU Grenoble, Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Foch [Suresnes], Service de pédiatrie (CHU de Dijon), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Immunologie clinique [CHU St-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Médecine interne et immunologie clinique [Rennes] = internal medicine and clinical immunology [Rennes], CHU Pontchaillou [Rennes], Service d'Immunologie Clinique et de Médecine Interne, Centre National de Référence des Maladies Auto-immunes Rares, Hôpitaux Universitaires de Strasbourg, Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Claude Huriez [Lille], CHU Lille, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), 'Personal Protection Against Vectors' working group (PPAV), PPAV working group, cellules dendritiques et greffes (JE 2448), Université de Tours (UT), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service de Médecine Interne, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Médecine interne, maladies infectieuses, immunologie clinique, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut d’Hémato-Oncologie Pédiatrique, INSERM U1012, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Internal Medicine, Paris, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de Génie Electrique de Grenoble (G2ELab), 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]), CHU Clermont-Ferrand, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Dept of Physiology, McGill University = Université McGill [Montréal, Canada], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], American Memorial Hospital, American Memory Hospital, Department of Clinical Immunology, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service Immuno Hémato-Onco Pédiatrique, Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, Service Hématologie Infantile, CHU Amiens-Picardie, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Département de Médecine Interne, Immunologie clinique et maladies infectieuses [CHU Reims], Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de médecine de l'enfant et de l'adolescent [CHU Rennes], Clinical Haematology, CHU Hôtel-Dieu, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], French Ministry of Health, LFB, GlaxoSmithKlineGlaxoSmithKline, CSL BehringCSL Behring, ShireShire, Octapharma, Binding Site, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Chaire Médecine expérimentale (A. Fischer), Service de Génétique Cytogénétique et Embryologie [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), GREPI, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), 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)-Université Paris Diderot - Paris 7 (UPD7), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie pédiatrique, CHU Toulouse [Toulouse], CHU Saint-Etienne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de médecine de l'enfant et de l'adolescent, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], 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)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Nutrition et Neurobiologie intégrée (NutriNeur0), Ecole nationale supérieure de chimie, biologie et physique-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), 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 Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Sud, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose et Progression tumorale (CRCNA / Equipe 9), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Service de médecine interne, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Tours, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre collaborateur de l'OMS Listeria - Biologie des Infections (CCOMS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], McGill University, Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Centre Hospitalier Universitaire d'Amiens (CHU), centre hospitalier universitaire amiens, CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)
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0301 basic medicine ,Primary Immunodeficiency Diseases ,medicine.medical_treatment ,Genetic counseling ,Immunology ,Genomics ,Bioinformatics ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Humans ,Immunology and Allergy ,Medicine ,Genetic Testing ,Registries ,Retrospective Studies ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,business.industry ,Common variable immunodeficiency ,Retrospective cohort study ,medicine.disease ,Phenotype ,3. Good health ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,030104 developmental biology ,Identification (biology) ,France ,business ,030215 immunology - Abstract
International audience; To the Editor:Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1 with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). [...]
- Published
- 2019
70. POS0095 DEVELOPPING A SCORE TO PREDICT PRECLINICAL INTERSTITIAL LUNG DISEASE IN PATIENTS WITH RHEUMATOID ARTHRITIS – A CROSS-SECTIONAL STUDY FROM THE ESPOIR COHORT
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Bruno Fautrel, R.M. Flipo, Bruno Crestani, Philippe Dieudé, Francis Berenbaum, Benjamin Granger, Raphael Borie, B. Combe, G. Carvajal Alegria, Esther Ebstein, Caroline Kannengiesser, Catherine Boileau, Xavier Mariette, Arnaud Constantin, F. Louis Sidney, Pierre-Antoine Juge, A. Saraux, Joanna Kedra, Olivier Vittecoq, J. Sibilia, and Marie-Pierre Debray
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medicine.medical_specialty ,Cross-sectional study ,business.industry ,Immunology ,Interstitial lung disease ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Rheumatology ,Rheumatoid arthritis ,Internal medicine ,Cohort ,medicine ,Immunology and Allergy ,In patient ,business - Abstract
Background:Interstitial lung disease (ILD) is an extra-articular manifestation of rheumatoid arthritis (RA) detected in 20% to 60% of patients with RA on high-resolution computed-tomography (HRCT) chest scan and is clinically significant in near 10%. Despite a high morbi-mortality rate, a definite strategy for preclinical ILD screening in patients with RA remains to be determined. To date, several factors have been reported to increase the risk of RA-ILD occurrence (i.e. older age at RA onset, ACPA positivity, male sex, RA disease activity, the MUC5B rs35705950 promoter variant...). However, none of these risk factors has been validated in a prospective cohort of patients with RA. The ESPOIR prospective cohort includes patients aged 18 to 70 years with recent arthritis (less than 6 months) and a definite or probable diagnosis of RA.Objectives:To identify in the ESPOIR cohort factors associated with ILD after at least 10 years of RA duration in order to develop a predictive score to identify patients with preclinical RA-ILD.Methods:An ILD detection by chest HRCT scan was systematically offered to every patient with definite RA after at least 10 years-follow-up. Chest HRCT scans were centrally reviewed by an experienced radiologist. Potential predictors of ILD were prospectively collected from baseline to the date of the HRCT scan, and all included patients were genotyped for MUC5B rs35705950. To take into account repeated measures, trajectories were determined for disease activity, C reactive protein, smoking, treatment exposure (i.e. prednisone, methotrexate [MTX] and biological disease modifying anti-rheumatic drugs [bDMARDs]). A logistic model was used to identify independent predictors for the occurrence of ILD on HRCT scans. Confidence intervals were estimated using sampling methods. A predictive score for preclinical ILD occurrence was developed based on the identified predictors.Results:163 RA patients according to 2010 ACR/EULAR classification criteria, none of whom had pulmonary symptoms, were investigated with a chest HRCT scan (128 women (78.5%), mean RA duration 13.7 ± 1.1 years, age at inclusion 47.6 y/o ± 10.4, mean disease activity score [DAS]-28 during follow up was 3.1 ± 1.0). ILD was detected in 31 patients (19.0%). The MUC5B rs35705950 minor allele frequency (MAF) was 22.2% and 10.0% in the RA-ILD and RA-noILD populations, respectively (OR univariate=2.6 CI95% [1.2-5.5], P=0.01). After logistic regression, independent predictors for preclinical RA-ILD were male sex (OR=3.9 CI95% [1.4-11.4]), older age at RA onset (OR=1.1 per year CI95% [1.0-1.2]), mean DAS-28 score during the follow-up (OR=2.0 CI95% [1.2-3.4]) and MUC5B rs35705950 T risk allele (OR=3.7 CI95% [1.4-10.4]) (Figure 1). No influence of the use of RA-related drugs (prednisone, MTX or bDMARDs) was identified as risk factor. The logistic model could predict preclinical ILD occurrence after 13 years of RA duration with an AUC=0.82 CI95% (0.72-0.91). A predictive score for preclinical RA-ILD based on the 4 identified predictive risk factors was developed (Sensitivity 80%, Specificity 56%).Figure 1.Factors independently associated with preclinical ILD after 13 years of RA durationConclusion:In this cross-sectional study of the prospective ESPOIR cohort, we identified clinical and genetic predictors for ILD after 13 years of RA duration. We developed a predictive score that could improve risk stratification for preclinical RA-ILD and help physicians identify patients with RA in whom a HRCT scan should be performed.Disclosure of Interests:Pierre-Antoine Juge Consultant of: BMS, Benjamin Granger: None declared, Marie-Pierre Debray: None declared, Esther Ebstein: None declared, Fabienne Louis Sidney: None declared, Joanna KEDRA: None declared, Raphael Borie: None declared, Arnaud Constantin Consultant of: Bristol-Meyers Squibb, Chugai, Roche, Abbvie, MSD, Pfizer, and UCB, Bernard Combe Consultant of: Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chigai, and Sanofi, Grant/research support from: Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chugai, and Sanofi, René-Marc Flipo Consultant of: Bristol-Meyers Squibb, Roche, Chugai, Abbvie, and Pfizer, Grant/research support from: Roche, Chugai, Abbvie, and Pfizer, Xavier Mariette Consultant of: Bristol-Meyers Squibb, GSK, Janssen, Pfizer, and UCB, Olivier VITTECOQ Consultant of: Bristol Myers Squibb, Roche, Chugai, MSD, Novartis, Pfizer, Abbvie, and Lilly, Alain Saraux Consultant of: Roche, Chugai, and Bristol-Meyers Squibb, Grant/research support from: Roche, Chugai, and Bristol-Meyers Squibb, Guillermo CARVAJAL ALEGRIA: None declared, Jean Sibilia Consultant of: Roche, Chugai, Bristol-Meyers Squibb, UCB, GSK, LFB, Actelion, Pfizer, MSD, Novartis, Amgen, Hospira, AbbVie, Sandoz, Gilead, Lilly, Sanofi, Janssen, and Mylan, Francis Berenbaum Consultant of: Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Elli Lilly, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, Caroline Kannengiesser: None declared, Catherine Boileau: None declared, Bruno Crestani Consultant of: Boehringer Ingelheim, Roche, Sanofi, Apellis, Astra-Zeneca, Grant/research support from: MedImmune, Boehringer Ingelheim, Bruno Fautrel Consultant of: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, SOBI, UCB, Grant/research support from: AbbVie, MSD, Pfizer, Philippe Dieudé: None declared
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- 2021
71. Looking for somatic mutations in fibrosing interstitial lung diseases
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Catherine Boileau, Pierre-Antoine Juge, Ibrahima Ba, Raphael Borie, Bruno Crestani, Caroline Kannengiesser, and Philippe Dieudé
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Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Lung ,business.industry ,Somatic cell ,Fibrosis ,Text mining ,medicine.anatomical_structure ,Mutation ,medicine ,Humans ,Lung Diseases, Interstitial ,business - Published
- 2021
72. Prévalence de la pneumopathie interstitielle diffuse associée à la polyathrite rhumatoïde dans la cohorte Espoir et intérêt du génotypage de rs35705950
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G. Carvajal Alegria, F. Louis-Sydney, Raphael Borie, Catherine Boileau, Benjamin Granger, Bruno Crestani, Arnaud Constantin, Marie-Pierre Debray, J. Sibilia, R.M. Flipo, Olivier Vittecoq, Joanna Kedra, Bruno Fautrel, Francis Berenbaum, Esther Ebstein, Florence Tubach, Xavier Mariette, P.A. Juge, B. Combe, Caroline Kannengiesser, and Philippe Dieudé
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Rheumatology - Abstract
Introduction La pneumopathie interstitielle diffuse (PID) est une manifestation extra-articulaire frequente de la polyarthrite rhumatoide (PR) associee a une forte morbi-mortalite. La prevalence exacte de la PR-PID clinique ou infraclinique varie ainsi selon les etudes entre 20 et 60 % et depend de la methode de depistage et de sa temporalite par rapport au debut de la PR. Recemment, le variant du promoteur de MUC5B rs35705950 a ete associe a la presence d’une PID chez les patients atteints de PR. La cohorte ESPOIR a inclus et suivi des patients âges de 18 a 70 ans souffrant d’une PR recente probable ou certaine. Nos objectifs etaient : – d’estimer la prevalence de la PID infraclinique au sein de la cohorte ESPOIR apres au moins 10 ans d’evolution ; – d’evaluer l’interet du genotypage de MUC5B rs35705950 comme marqueur predictif de survenue d’une PR-PID. Patients et methodes Dans cette etude transversale au sein de la cohorte ESPOIR, un depistage d’une PID par scanner thoracique haute-resolution (HRCT) a ete systematiquement propose aux patients inclus dans ESPOIR apres 13 ans de suivi. Une lecture centralisee des HRCT a ete realisee par un radiologue expert qui a classe les patients en fonction de la presence ou l’absence de PID. En cas de PID, l’extension et l’aspect ont ete evalues. Deux patients issus de la cohorte ESPOIR precedemment decedes d’une PR-PID ont ete inclus dans l’analyse afin d’identifier les facteurs prognostiques. Tous les patients inclus ont ete genotypes pour MUC5B rs35705950. Une regression logistique a ete utilisee afin d’identifier les facteurs collectes a l’inclusion dans ESPOIR et predictifs de la presence d’une PID apres au moins 10 ans d’evolution de la PR. Les intervalles de confiance ont ete estimes par methode d’echantillonnage. Resultats Parmi les 170 patients explores par HRCT [133 femmes (78,2 %), duree moyenne de la PR 13,7 ± 1,1 ans], une PID infraclinique etait detectee chez 31 patients (18,2 %) : 19 femmes (61,3 %), âge moyen 67,9 ± 8,7 ans, âge moyen au diagnostic de PR 54,3 ± 8,6 ans. L’etendue de la PID etait 10 % chez 9 patients (5,3 %). Quatre patients presentaient un aspect de pneumopathie interstitielle commune, 4 patients presentaient un aspect de pneumopathie interstitielle non specifique. Des signes scannographiques de fibrose pulmonaire etaient detectes chez 16 patients (9,4 %). Parmi les europeens caucasiens (n = 160), la frequence de l’allele mineur de MUC5B rs35705950 etait de 26,5 % chez les patients PR-PID et de 8,9 % chez les patients PR-non PID (OR = 6,0 ; IC95 %(1,2–7,2)). Apres regression logistique, les facteurs presents au diagnostic de PR et predictifs de survenue d’une PID a 13 ans etaient le sexe masculin (OR = 2,6 IC95 %(1,0-6,6)), un âge au debut de la PR > 49 ans (OR = 5,2 IC95 %(2,0-15,1)), un nombre d’articulations gonflese >9 (OR = 2,9 IC95 %(1,2-7,2)), le caractere migrateur et non fixe des arthrites (OR = 3,4 IC95 %(1,4-8,7)) et l’allele a risque T de MUC5B rs35705950 (OR = 3,8 IC95 %(1,5-10,1)). Ce modele logistique permettait de predire la presence d’une PID apres au moins 10 ans d’evolution de la PR avec une aire sous la courbe = 0,80 IC95 %(0,72-0,90). Conclusion Dans la cohorte ESPOIR, apres au moins 10 ans d’evolution de la PR, la prevalence de la PID infraclinique etait de 18,2 %. Au diagnostic de PR, en association avec certaines donnees cliniques, le genotypage de MUC5B rs35705950 permet d’ameliorer la stratification des patients a risque de developper ulterieurement une PID.
- Published
- 2020
73. LethalALAS2mutation in males X-linked sideroblastic anaemia
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Anne Lambilliotte, Isabelle Callebaut, Christian Rose, Caroline Kannengiesser, Laurent Pascal, Claire Oudin, Laurent Gouya, and Martine Fournier
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0301 basic medicine ,Genetics ,business.industry ,Hematology ,Bioinformatics ,ALAS2 ,X-linked sideroblastic anaemia ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mutation (genetic algorithm) ,Medicine ,business ,030215 immunology - Published
- 2016
74. Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain
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Patrick Revy, Laurent Jullien, Laetitia Kermasson, Isabelle Callebaut, Arturo Londoño-Vallejo, Caroline Kannengiesser, Thierry Leblanc, Valérie Cormier-Daire, Jean Soulier, and Jean-Pierre de Villartay
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0301 basic medicine ,Genetics ,Mutation ,biology ,Protein domain ,Helicase ,Hoyeraal-Hreidarsson syndrome ,Compound heterozygosity ,medicine.disease ,medicine.disease_cause ,Molecular biology ,Exon skipping ,Telomere ,03 medical and health sciences ,030104 developmental biology ,biology.protein ,medicine ,Genetics (clinical) ,Dyskeratosis congenita - Abstract
The DNA helicase RTEL1 participates in telomere maintenance and genome stability. Biallelic mutations in the RTEL1 gene account for the severe telomere biology disorder characteristic of the Hoyeraal-Hreidarsson syndrome (HH). Here, we report a HH patient (P4) carrying two novel compound heterozygous mutations in RTEL1: a premature stop codon (c.949A>T, p.Lys317*) and an intronic deletion leading to an exon skipping and an in-frame deletion of 25 amino-acids (p.Ile398_Lys422). P4's cells exhibit short and dysfunctional telomeres similarly to other RTEL1-deficient patients. 3D structure predictions indicated that the p.Ile398_Lys422 deletion affects a part of the helicase ARCH domain, which lines the pore formed with the core HD and the iron-sulfur cluster domains and is highly specific of sequences from the eukaryotic XPD family members.
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- 2016
75. Anémies microcytaires rares
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Hervé Puy, Zoubida Karim, Caroline Kannengiesser, and Hana Manceau
- Subjects
0301 basic medicine ,Serine protease ,Genetics ,Anemia ,Microcytic anemia ,General Medicine ,Iron deficiency ,Biology ,medicine.disease ,Transmembrane protein ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Hepcidin ,hemic and lymphatic diseases ,medicine ,biology.protein ,Bone marrow ,Gene - Abstract
Microcytic anemia is often due to disorder of globin genes. Here, we focus on rare monogenic microcytic anemias, We describe the diferent congenital forms that are due to mutations in genes implicated in iron homeostasis, the heme biosynthesis pathway, the cluster Fe-S biosynthesis pathway andmitochondrial proteins biosynthesis pathway. Among rare congenital microcytic anemias, most frequent forms are non syndromic sideroblastic anemias and iron refractory iron deficiency anemias (IRIDA). Sideroblastic anemias is characterized by mitochondrial iron overload and presence of ring sideroblasts in patient bone marrow.. IRIDA results from bi-allelic mutations of TMPRSS6 gene encoding Matriptase-2. Matriptase-2 protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. The next generation sequencing would be helpful to identify the genes implicated in unexplained rare anemias.
- Published
- 2016
76. GermlineSFTPA1mutation in familial idiopathic interstitial pneumonia and lung cancer
- Author
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Serge Amselem, Alice De Ligniville, Dominique Valeyre, Nadia Nathan, Bruno Copin, Annick Clement, Nathalie Kuziner, Thierry Chinet, Valérie Nau, Florence Dastot-Le Moal, Raphael Borie, Clément Picard, Lamisse Mansour Hendili, Violaine Giraud, Hilario Nunes, Laurent Gouya, Aurore Coulomb, Louis-Jean Couderc, Bruno Crestani, Martine Reynaud Gaubert, Sylvie Tissier, Maud Simansour, Marie Legendre, Philippe Duquesnoy, Caroline Kannengiesser, Laurie Galeron, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie et d'Oncologie Thoracique [AP-HP Hôpital Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Service de pneumologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), 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, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord [CHU - APHM], Service de pneumologie et oncologie thoracique [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre Hospitalier Universitaire Ambroise Paré (CHU Ambroise Paré), Service de Pneumologie [Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Faculté de Médecine Xavier Bichat, Service de Pneumologie et Centre de Compétence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat, Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Service de Pneumologie pédiatrique [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 de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-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)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de génétique et embryologie médicales [CHU Trousseau], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [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)-CHU Trousseau [APHP], Service de pathologie [CHU Trousseau], COMBE, Isabelle, Service de pneumologie, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Service des maladies respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, AP-HP, Service d'Hématologie Biologique, Hôpital Robert-Debré, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Excellence GR-Ex ' The red cell : from genesis to death ', and PRES Sorbonne Paris Cité
- Subjects
Male ,0301 basic medicine ,Pathology ,Lung Neoplasms ,Disease ,ABCA3 ,medicine.disease_cause ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,SFTPA2 ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Missense mutation ,Genetics (clinical) ,0303 health sciences ,Mutation ,Pulmonary Surfactant-Associated Protein A ,General Medicine ,Middle Aged ,respiratory system ,Pedigree ,3. Good health ,medicine.anatomical_structure ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Adenocarcinoma ,Female ,Adult ,medicine.medical_specialty ,Mutation, Missense ,Biology ,03 medical and health sciences ,Germline mutation ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Idiopathic Interstitial Pneumonias ,Lung cancer ,Molecular Biology ,Idiopathic interstitial pneumonia ,Germ-Line Mutation ,Aged ,030304 developmental biology ,Lung ,business.industry ,Cancer ,Sequence Analysis, DNA ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Gene Expression Regulation ,030228 respiratory system ,Immunology ,biology.protein ,business ,030215 immunology - Abstract
Background: Idiopathic interstitial pneumonia (IIP) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality. They have been associated with an increased frequency of lung cancer. A genetic cause is identified in up to 20% of familial cases, telomerase and surfactant genes (SFTPA2, SFTPB, SFTPC, ABCA3) mutations being the first etiologies. Objectives:This study investigates the implication of SFTPA1 (NM_005411) in 12 families affected by IPF and lung cancer. Methods:SFTPA1 was sequenced by Sanger method in 12 unrelated index cases. An informed signed consent was obtained for each patient. New SFTPA1 variations were studied with functional experimentations. Results: A heterozygous missense disease-causing mutation (p.Trp211Arg, W211R), in SFTPA1, that encodes the Surfactant Protein (SP)-A1, was identified in a large family. The affected members, aged 7 months to 59 years, presented with various forms of IIP, and adenocarcinoma. The W211R mutation segregated in a dominant pathway with the disease. The mutation involved an amino-acid that is located in the carbohydrate recognition domain (CRD) of SP-A1 and involved a residue invariant throughout evolution in SP-A1, but also in SP-A2 and in other CRD-containing proteins. The W211R mutation impaired SP-A1 secretion, and an abnormal expression pattern of SP-A was found in the alveolar epithelium of lung tissue from a patient carrying the SFTPA1 mutation. Conclusion: This first report of the involvement of SFTPA1 in a Mendelian disorder unveils the key role of SP-A1 in the pathophysiology of IIP from infancy to elderly, and open up a new field of research on the mechanisms involved in IIP and lung cancer.
- Published
- 2016
77. Methotrexate and rheumatoid arthritis associated interstitial lung disease
- Author
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Kevin D. Deane, Eric L. Matteson, Leticia Kawano-Dourado, Yannick Allanore, René-Marc Flipo, Christophe Richez, Sébastien Ottaviani, David A. Schwartz, Karina Bonfiglioli, Montserrat I González-Pérez, Yurdagul Uzunhan, Gabriel Thabut, Jorge Rojas Serrano, Raphael Borie, Thierry Schaeverbeke, Benoit Wallaert, Ivan O. Rosas, Ramcés Falfán-Valencia, Lorenzo Cavagna, Marie-Elise Truchetet, Pascal Richette, Marco Sebastiani, Tracy J. Doyle, Emanuele Bozzalla Cassione, Gouri Koduri, Esther Ebstein, Jay H. Ryu, Lidwine Wemeau-Stervinou, Huguette Lioté, Dominique Valeyre, Pedro Rodríguez-Henriquez, Raphaël Porcher, Bruno Crestani, Jessica Lau, Steven Gazal, Marie-Christophe Boissier, Marie-Pierre Debray, Hilario Nunes, Mayra Mejía, Ivette Buendía-Roldán, Sylvain Marchand-Adam, Robert Vassallo, Andreina Teresa Manfredi, Nathalie Saidenberg-Kermanac’h, Joshua J. Solomon, Claire Dromer, Joyce S. Lee, Gloria Pérez-Rubio, Catherine Boileau, V. Michael Holers, Pierre-Antoine Juge, Marcio Valente Yamada Sawamura, Ronaldo Adib Kairalla, Caroline Kannengiesser, and Philippe Dieudé
- Subjects
030203 arthritis & rheumatology ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Extramural ,business.industry ,Diffuse lung disease ,respiratory system ,behavioral disciplines and activities ,Article ,respiratory tract diseases ,Arthritis, Rheumatoid ,body regions ,03 medical and health sciences ,Methotrexate ,0302 clinical medicine ,Antirheumatic Agents ,Case-Control Studies ,Family medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Lung Diseases, Interstitial ,business ,Lung - Abstract
Background: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed. Objectives: We aimed to evaluate the association of antecedent MTX use with development of RA-ILD. Methods: Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. Results: Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; P Conclusion: Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD. Disclosure of Interests: Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodriguez Henriquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramces Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoit Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Liote: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphael Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieude: None declared
- Published
- 2020
78. The MUC5B promoter risk allele for idiopathic pulmonary fibrosis predisposes to asbestosis
- Author
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Philippe Dieudé, Ivo A. Wiertz, Mark G J P Platenburg, Bruno Crestani, Joanne J. van der Vis, Jan C. Grutters, Caroline Kannengiesser, Raphael Borie, Coline H.M. van Moorsel, and Jacobus A. Burgers
- Subjects
Pulmonary and Respiratory Medicine ,Asbestos industry ,business.industry ,Nothing ,Law ,Asbestosis ,Risk allele ,Conflict of interest ,medicine ,medicine.disease ,business ,Production team ,Interstitial pneumonitis - Abstract
Asbestosis is a fibrosing interstitial pneumonitis, which can develop following occupational asbestos exposure and a lengthy latency period [1]. Even after strict regulations on the asbestos industry, an estimated 3400 individuals worldwide died as a consequence of asbestosis in 2017 [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr Platenburg has nothing to disclose. Conflict of interest: Dr Wiertz has nothing to disclose. Conflict of interest: Dr van der Vis has nothing to disclose. Conflict of interest: Dr Crestani has nothing to disclose. Conflict of interest: Dr Borie reports grants and personal fees from Roche, grants and personal fees from Boerhinger Ingelheim, outside the submitted work. Conflict of interest: Philippe Dieude Conflict of interest: Dr Kannengiesser has nothing to disclose. Conflict of interest: D. Burgers reports grants from MSD, other from Roche, other from AstraZeneca, other from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr Grutters has nothing to disclose. Conflict of interest: Dr van Moorsel has nothing to disclose.
- Published
- 2020
79. Pulmonary fibrosis: Genetic analysis of telomere-related genes, telomere length measurement-or both?
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Elisabetta A. Renzoni, Caroline Kannengiesser, and Raphael Borie
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,business.industry ,Interstitial lung disease ,Telomere ,medicine.disease ,Prognosis ,Genetic analysis ,Idiopathic Pulmonary Fibrosis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Pulmonary fibrosis ,Medicine ,Humans ,business ,Gene ,Telomerase ,Telomere Shortening - Published
- 2018
80. Multidisciplinary team dedicated to suspected heritable pulmonary fibrosis
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Nadia Nathan, Serge Amselem, Ralph Epaud, Philippe Dieudé, Laurent Gouya, Bruno Crestani, Vincent Cottin, Olivier Brugière, Pascale Fanen, Lidwine Wemeau-Stervinou, Annick Clement, Caroline Kannengiesser, Flore Sicre de Fontbrune, Clairelyne Dupin, Diane Bouvry, and Raphael Borie
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Mean age ,Lung biopsy ,medicine.disease ,Multidisciplinary team ,Patient management ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Pulmonary fibrosis ,medicine ,Lung transplantation ,030212 general & internal medicine ,Intensive care medicine ,business ,Genetic testing - Abstract
Genetic testing is proposed for suspected cases of pulmonary fibrosis of genetics origin but clinicians and patients need advice about the related diagnostic and management issues. Because multidisciplinary team (MDT) has been shown to improve accuracy of ILD diagnosis, we evaluated the feasibility of an MDT dedicated to the indication and interpretation of genetic testing. The MDT met monthly, included pneumologists experts in ILD in adults, children, geneticists, radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend. Since 2016, 70 patients (37 males, 33 females) were discussed, from 31 different centers (7 countries). Mean age was 46.4 years [0-71] including 3 patients The MDT therapeutic proposals were: antifibrotic drugs (n=23), best supportive care (n=4), surgical lung biopsy (n=2), steroids (n=7), lung transplantation (n=16), or watch and wait (n=9). Our experience shows that a dedicated MDT with genetic analysis is feasible including patients of all ages and provides a unique opportunity to improve knowledge and to adapt patient management and therapy.
- Published
- 2018
81. Lung disease caused by non-null ABCA3 mutations: long-term follow-up
- Author
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Stylianos Loukides, Maria Maniati, Angeliki Androu, Konstantinos Kagouridis, Effrosyni D. Manali, Periklis G. Foukas, Bruno Crestani, Nikolaos Roussakis, Lykourgos Kolilekas, Penelope Korkolopoulou, Serge Amselem, Maria Kallieri, Periklis Tomos, Marie Legendre, Raphael Borie, Ioanna Korbila, Nadia Nathan, Ioannis Tomos, Spyros Papiris, Aurore Coulomb-L'Hermine, Stylianos Argentos, Matthias Griese, Andrea Schams, Anna Karakatsani, Caroline Kannengiesser, Georgios N. Koutsocheras, and Theofanis Tsiligiannis
- Subjects
Oncology ,medicine.medical_specialty ,biology ,Lung disease ,business.industry ,Long term follow up ,Internal medicine ,Null (mathematics) ,biology.protein ,medicine ,ABCA3 ,business - Published
- 2018
82. Functional assessment of newly identified SFTPA1 and SFTPA2 mutations in patients with idiopathic interstitial pneumonia (IIP) and lung cancer
- Author
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Valérie Nau, Emilie Filhol-Blin, Violaine Giraud, Laurent Gouya, Philippe Duquesnoy, Christophe Delacourt, Afifaa Butt, Jean-Charles Dalphin, Julie Traclet, Philippe Reix, Hilario Nunes, Bruno Crestani, Juliette Albuisson, Serge Amselem, Paul De Vuyst, Bruno Copin, Marie Legendre, Carine Gomez, Grégoire Prévot, Diane Bouvry, Raphael Borie, Clément Picard, Florence Dastot-Le Moal, Vincent Cottin, Caroline Kannengiesser, Nadia Nathan, Keren Borensztajn, Aurore Coulomb L'Hermine, Annick Clement, Kais Ahmad, Nathalie Allou, and Martine-Louise Reynaud-Gaubert
- Subjects
Pathology ,medicine.medical_specialty ,Lung ,business.industry ,medicine.disease ,Penetrance ,3. Good health ,Alveolar cells ,medicine.anatomical_structure ,SFTPA2 ,medicine ,Adenocarcinoma ,Secretion ,Lung cancer ,business ,Idiopathic interstitial pneumonia - Abstract
Background: Heterozygous mutations in the SFTPA1 and SFTPA2 genes, encoding the surfactant protein SP-A1 and SP-A2 have been associated with rare forms of familial IIP and lung adenocarcinoma. We previously described 11 new heterozygous SFTPA1 and SFTPA2 variations in 13 unrelated patients including one newborn. The study aims to analyze the pathogenicity of those variations. Methods: We first analyzed the intrafamilial segregation of the identified variations with IIP and lung cancer. The production and the secretion of the mutant proteins were subsequently studied in HEK293T cells transiently expressing the SP-A proteins carrying the variations. Finally, SP-A expression was assessed on lung tissues of the patients. Results: In the studied families (38 adults, 3 children), the variations segregated with either IIP and/or lung cancer (37%) with an incomplete penetrance of the disease phenotype. The mean age at onset of the IIP was 45 years (0-68). Nine of the variations were located in the highly conserved carbohydrate recognition domain of the protein. In vitro, the mutant proteins were produced but their secretion was absent (n=9) or altered (n=2). The lung expression of SP-A studied in 3 unrelated patients showed an increased expression of SP-A in the cytoplasm of hypertrophic type 2 alveolar cells. Discussion and conclusion: The 11 identified SFTPA1 and SFTPA2 variations are pathogenic. They are associated with IIP and with an increased risk of lung cancer. They were identified mainly in adults but also in children. The pathophysiological consequences of their abnormal secretion/expression remain to be elucidated.
- Published
- 2018
83. TERT/TERC mutations in a Greek cohort of suspected genetic pulmonary fibrosis patients
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Katerina Vlami, Philippe Dieudé, Demosthenes Bouros, Chrysa Bazaka, Aikaterini Markopoulou, Lykourgos Kolilekas, Paschalina Giouleka, Konstantinos Kagouridis, Thomas Raptakis, Athina Gogali, Athanasios Konstantinidis, Nadia Nathan, Stylianos Loukides, Maria Maniati, Evangelos Bouros, Vasileios Tzilas, Aggeliki Charitou, Mina Gaga, Zoe Daniil, Ilias Papanikolaou, Paschalis Steiropoulos, Bruno Crestani, Athina Trachalaki, Maria Kallieri, Effrosyni D. Manali, Andriana I. Papaioannou, Spyros Papiris, Despoina Papakosta, Areti Xyfteri, Georgia Papadaki, Catherine Boileau, Argyrios Tzouvelekis, Evangelia Fouka, Anna Karakatsani, Caroline Kannengiesser, Patrick Revy, Eleni Stagaki, Katerina M. Antoniou, Anastasia Papaporfyriou, Ioanna Korbila, Ioannis Tomos, Raphael Borie, and Panagiotis Lyberopoulos
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medicine.medical_specialty ,business.industry ,Internal medicine ,Pulmonary fibrosis ,Cohort ,medicine ,medicine.disease ,business - Published
- 2018
84. Genetic landscape of adult Langerhans cell histiocytosis with lung involvement
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Emmanuelle Clappier, Sylvie Chevret, Abdellatif Tazi, Alexandre How-Kit, Véronique Meignin, Emmanuelle Bugnet, Caroline Kannengiesser, Gwenaël Lorillon, Samia Mourah, Alain Haziot, Céleste Lebbé, Fanélie Jouenne, Aurélie Sadoux, Dominique Gossot, and Shannon Cohen
- Subjects
Adult ,Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Disease ,Adult Langerhans Cell Histiocytosis ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,MAP2K1 ,medicine ,Humans ,Clinical significance ,Child ,Lung ,Genotyping ,Mutation ,business.industry ,Proportional hazards model ,High-Throughput Nucleotide Sequencing ,Histiocytosis, Langerhans-Cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,KRAS ,business - Abstract
The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRASQ61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.
- Published
- 2019
85. Regulator of telomere length 1 (
- Author
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Raphael, Borie, Diane, Bouvry, Vincent, Cottin, Clement, Gauvain, Aurélie, Cazes, Marie-Pierre, Debray, Jacques, Cadranel, Philippe, Dieude, Tristan, Degot, Stephane, Dominique, Anne Sophie, Gamez, Madeleine, Jaillet, Pierre-Antoine, Juge, Arturo, Londono-Vallejo, Arnaud, Mailleux, Hervé, Mal, Catherine, Boileau, Christelle, Menard, Hilario, Nunes, Gregoire, Prevot, Sebastien, Quetant, Patrick, Revy, Julie, Traclet, Lidwine, Wemeau-Stervinou, Marie, Wislez, Caroline, Kannengiesser, and Bruno, Crestani
- Subjects
Adult ,Aged, 80 and over ,Lung Diseases ,Male ,Heterozygote ,Vital Capacity ,DNA Helicases ,Sequence Analysis, DNA ,Middle Aged ,Pedigree ,Phenotype ,Gene Expression Regulation ,Mutation ,Humans ,Exome ,Female ,Lung Diseases, Interstitial ,Telomerase ,Aged ,Follow-Up Studies - Abstract
Regulator of telomere length 1 (
- Published
- 2018
86. Safety and efficacy of pirfenidone in patients carrying telomerase complex mutation
- Author
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Anne Gondouin, Martine Reynaud-Gaubert, Eline Magois, Anne Sophie Gamez, Hilario Nunes, Maria Molina Molina, Sylvain Marchand-Adam, Aurélien Justet, Lidwine Wemeau, Raphael Borie, Gabriel Thabut, Vincent Cottin, Caroline Kannengiesser, Bruno Crestani, Grégoire Prévot, Cécile Tromeur, Jacques Cadranel, Spyros Papiris, Effrosyni D. Manali, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [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), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Pneumology and Intensive Care, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département des Maladies Respiratoires [Montpellier], Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Microbes évolution phylogénie et infections (MEPHI), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Département Hospitalo-Universitaire Fibrosis, Inflammation, Remodeling in cardiovascular, respiratory and renal diseases (Paris), LabEx Inflamex, Université Sorbonne Paris Cité (USPC), Service de Pneumologie [Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Centre de Compétence pour les Maladies Pulmonaires Rares, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Service de Pneumologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), UFR SMBH-Université Paris 13 (UP13), Université de Brest (UBO), CHU Toulouse [Toulouse]-Hôpital Larrey, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre de Compétence pour les Maladies Pulmonaires Rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
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Male ,Pulmonary and Respiratory Medicine ,Oncology ,Heterozygote ,medicine.medical_specialty ,Telomerase ,Pyridones ,Pulmonary Fibrosis ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Internal medicine ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Lung function ,ComputingMilieux_MISCELLANEOUS ,Aged ,Retrospective Studies ,Greece ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Retrospective cohort study ,Pirfenidone ,Middle Aged ,respiratory system ,humanities ,3. Good health ,body regions ,030228 respiratory system ,Multicenter study ,Spain ,Mutation ,Mutation (genetic algorithm) ,RNA ,Female ,France ,Patient Safety ,business ,medicine.drug - Abstract
In this retrospective study, a beneficial effect of pirfenidone on lung function decline could not be demonstrated in patients carrying TERT/TERC mutation
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- 2018
87. MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease
- Author
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Yaping Wang, Annick Clement, Nadia Nathan, Joanne J. van der Vis, Huguette Lioté, Aryeh Fischer, Dominique Valeyre, David A. Schwartz, Jan C. Grutters, Timothy B Niewold, Michael A. Nalls, Ivette Buendía-Roldán, Dimitrios Boumpas, Vincent Cottin, Marie-Christophe Boissier, Theofanis Karageorgas, Mayra Mejía, Yaël A de Man, Kevin D. Deane, Effrosyni D. Manali, Katarina M. Antoniou, Joshua J. Solomon, Jay H. Ryu, Pierre-Antoine Juge, Martin Soubrier, Jean Sibilia, Hilario Nunes, Marie-Pierre Debray, Christophe Richez, Spyros Papiris, Steven Gazal, Catherine Boileau, Deborah Assayag, Nathalie Saidenberg-Kermanac’h, Tasha E. Fingerlin, Claire Dromer, Marvin I. Schwarz, Esther Ebstein, Michael Holers, Tracy J. Doyle, Ivan O. Rosas, Bruno Crestani, Hiroshi Furukawa, Evgenia Dobrinskikh, Cornelis Blauwendraat, Paul J. Wolters, Naoyuki Tsuchiya, Thierry Schaeverbeke, Ramcés Falfán-Valencia, Lidwine Wemeau-Stervinou, Gabriel Thabut, Shigeto Tohma, Coline H.M. van Moorsel, Montserrat I González-Pérez, Andrew J. Gross, Benoit Wallaert, Shomi Oka, Caroline Kannengiesser, Joyce S. Lee, Enrique Ambrocio-Ortiz, Aline Frazier, Sylvain Marchand-Adam, René-Marc Flipo, Eric L. Matteson, Pascal Richette, S. Amselem, Raphael Borie, Jorge Rojas-Serrano, Yannick Allanore, Sébastien Ottaviani, Philippe Dieudé, Avram D Walts, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Colorado School of Medicine, Université de Tsukuba = University of Tsukuba, Sagamihara National Hospital [Kanagawa, Japan], Harvard T.H. Chan School of Public Health, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Athens, 'Attikon' Hospital, National and Kapodistrian University of Athens (NKUA), University of Crete [Heraklion] (UOC), St. Antonius Hospital [Nieuwegein], Nanjing Medical University, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Avicenne [AP-HP], Physiopathologie, Cibles et Thérapies de la Polyarthrite Rhumatoïde, Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Lariboisière-Fernand-Widal [APHP], Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Hautepierre [Strasbourg], Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), CHU Bordeaux [Bordeaux], Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), CHU Trousseau [APHP], CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), National Jewish Health (NJH), Mayo Clinic and Mayo College of Medicine, Rochester, New York University School of Medicine, NYU System (NYU), McGill University = Université McGill [Montréal, Canada], University of California [San Francisco] (UC San Francisco), University of California (UC), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Societe Francaise de Rhumatologie, Club Rhumatismes Inflammation, la Chancellerie des Universites de Paris (legs Poix), Sorbonne Paris Cite (FPI-SPC Program), Agence Nationale de la Recherche ANR-10-LABX-46 ANR-10-EQPX-07-01 ANR-14-CE10-0006 ANR-10-INBS-09, France Genomique National Infrastructure, Pfizer, Chugai, Centre de Resources Biologiques Hopital Bichat Paris FranceFondation Arthritis, Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, National Heart, Lung, and Blood Institute (UH2/3-HL123442, R01-HL097163, R21/R33-HL120770, P01-HL092870, and K23-HL138131), National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR051461), National Institute of Allergy and Infectious Diseases (U01-AI101981), U.S. Department of Defense (W81XWH-17-1-0597), National Center for Advancing Translational Science (UCSF-CTI KL2TR000143), the Nina Ireland Program for Lung Health, the Intramural Research Program of the National Institute of Aging, part of the National Institutes of Health, Department of Health and Human Services (Z01-AG000949–02), and the Japanese Society for the Promotion of Science., Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), and Societe Francaise de Rhumatologie, Club Rhumatismes Inflammation, la Chancellerie des Universites de Paris (legs Poix), Sorbonne Paris Cite (FPI-SPC Program), Agence Nationale de la Recherche ANR-10-LABX-46 ANR-10-EQPX-07-01 ANR-14-CE10-0006 ANR-10-INBS-09, France Genomique National Infrastructure, Pfizer, Chugai, Centre de Resources Biologiques Hopital Bichat Paris France
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Male ,Lung Diseases ,medicine.medical_specialty ,Genotype ,[SDV]Life Sciences [q-bio] ,Population ,Arthritis ,behavioral disciplines and activities ,Gastroenterology ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Promoter Regions ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Genetic ,Internal medicine ,Gain of Function Mutation ,Odds Ratio ,Medicine ,Humans ,Genetic Predisposition to Disease ,Rheumatoid/complications/*genetics ,Risk factor ,education ,Aged ,030203 arthritis & rheumatology ,Lung/chemistry/pathology ,education.field_of_study ,business.industry ,Interstitial lung disease ,General Medicine ,Odds ratio ,respiratory system ,Middle Aged ,medicine.disease ,respiratory tract diseases ,3. Good health ,body regions ,Minor allele frequency ,030228 respiratory system ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Rheumatoid arthritis ,Female ,Interstitial/complications/*genetics ,Mucin-5B/analysis/*genetics ,business ,Idiopathic Pulmonary Fibrosis/genetics - Abstract
International audience; BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7x10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7x10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3x10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4x10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5x10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Societe Francaise de Rhumatologie and others.).
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- 2018
88. Évolution après transplantation pulmonaire pour fibrose chez les patients porteurs d’une mutation du complexe télomérase
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G. Prévot, A. Roux, Romain Lazor, Hervé Mal, Sylvain Marchand-Adam, J. Le Pavec, Raphael Borie, Caroline Kannengiesser, Jean-Marc Naccache, Johanna Claustre, Sandrine Hirschi, Vincent Cottin, Antoine Froidure, Martine Reynaud-Gaubert, Stéphane Jouneau, M. Phillips Houlbracq, Lidwine Wemeau-Stervinou, S. Park, Bruno Crestani, and Hilario Nunes
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Pulmonary and Respiratory Medicine - Abstract
Introduction Les patients atteints d’une pneumopathie interstitielle diffuse associee a une mutation d’un gene regulateur du complexe telomerase (TRG) semblent presenter une moins bonne survie et des complications hematologiques plus frequentes apres transplantation pulmonaire (TxP). L’objectif de cette etude etait de determiner l’evolution apres TxP de ces patients dans une cohorte francaise. Methodes Tous les patients porteurs d’une mutation d’un TRG ayant eu une TxP en France entre 2009 et 2017 ont ete identifies par les centres de transplantation et le reseau francais OrphaLung. Resultats Vingt-sept patients ont ete inclus, dont 67 % etaient des hommes, avec des mutations de TERT (n = 17), TERC (n = 6), et RTEL1 (n = 4). Avant la greffe, 19 (70 %) presentaient une atteinte hematologique, dont 6 un syndrome myelodysplasique et 14 une hepatopathie. L’âge median lors de la TxP etait de 54 (± 9) ans. Apres la TxP, tous les patients presentaient une anemie, 74 % une thrombopenie, et 54 % une neutropenie. Quatre patients ont presente des complications hepatiques severes : une hemochromatose post transfusionnelle, une fibrose hepatique et deux patients une hypertension portale. 26 % ont presente une dysfonction chronique du greffon dans un delai median de 2,1 (± 1,3) ans. Quinze receveurs sont decedes (56 %) au cours du suivi. La mediane de survie apres la TP etait de 4,4 ans. La presence d’une myelodysplasie avant la TxP etait associee a une diminution de la survie (p Conclusion La survie apres TxP des patients porteurs d’une mutation d’un TRG est comparable a celle des patients sans mutation. Une TxP est possible apres un bilan exhaustif des comorbidites extra-respiratoires et une prise en charge post-greffe adaptee. La presence d’un syndrome myelodysplasique avant la greffe doit faire rediscuter le projet de greffe.
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- 2019
89. Novel Microdeletions Affecting the GNAS Locus in Pseudohypoparathyroidism: Characterization of the Underlying Mechanisms
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Caroline Silve, Régis Coutant, Giovanna Mantovani, Joe T. R. Clarke, Arrate Pereda, Luisa de Sanctis, Agnès Linglart, Intza Garin, Francesca Elli, Paolo Bordogna, Guiomar Perez de Nanclares, Caroline Kannengiesser, Osnat Admoni, and Yardena Tenebaum-Rakover
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Adolescent ,Alu Elements ,Child ,Child, Preschool ,Cohort Studies ,Comparative Genomic Hybridization ,Female ,GTP-Binding Protein alpha Subunits, Gs ,Genetic Loci ,Humans ,Infant ,Molecular Diagnostic Techniques ,Pseudohypoparathyroidism ,Young Adult ,Gene Deletion ,Biochemistry ,Clinical Biochemistry ,Endocrinology ,Biochemistry (medical) ,Endocrinology, Diabetes and Metabolism ,Medicine (all) ,Genetic counseling ,Locus (genetics) ,Gs ,Internal medicine ,Chromogranins ,medicine ,GNAS complex locus ,Preschool ,Genetics ,biology ,Point mutation ,Gene rearrangement ,medicine.disease ,GTP-Binding Protein alpha Subunits ,Diabetes and Metabolism ,biology.protein ,Pseudopseudohypoparathyroidism ,Haploinsufficiency - Abstract
Pseudohypoparathyroidism type Ia (PHP1A) is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, multiple hormonal resistance, and features of Albright hereditary osteodystrophy. When the phenotype is present but not associated with hormonal resistance, it is called psedopseudohypoparathyroidism (PPHP). Both entities have been associated to GNAS haploinsufficiency, and are mostly caused by inherited inactivating mutations at GNAS gene that codes for the stimulatory alpha subunit of G protein, although the cause remains unidentified in approximately 30% of patients.The aims of our work were 1) to identify GNAS locus defects in 112 patients with clinical diagnosis of PHP1A/PPHP and no point mutations at GNAS, to improve molecular diagnostic and genetic counseling; 2) to outline the underlying molecular mechanism(s).Methylation-specific-multiplex ligation-dependent probe amplification, qPCR, array comparative genomic hybridization, and long-PCR were used to search for genomic rearrangements at chromosome 20q and to identify their boundaries. We used different bioinformatic approaches to assess the involvement of the genomic architecture in the origin of the deletions.We discovered seven novel genomic deletions, ranging from 106-bp to 2.6-Mb. The characterization of five of seven deletion breakpoints and the definition of the putative molecular mechanisms responsible for these rearrangements revealed that Alu sequences play a major role in determining the genetic instability of the region.We observed that deletions at GNAS locus represent a significant cause of PPHP/PHP1A and that such defects are mostly associated with Alu-mediated recombination events. Their investigation revealed to be fundamental as, in some cases, they could be misdiagnosed as imprinting defects.
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- 2015
90. Familial pulmonary fibrosis
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Caroline Kannengiesser, Nadia Nathan, Bruno Crestani, Pauline Pradere, Raphael Borie, and L. Tabèze
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Pulmonary and Respiratory Medicine ,Mutation ,Telomerase ,Disease ,Biology ,medicine.disease ,medicine.disease_cause ,Idiopathic Pulmonary Fibrosis ,Idiopathic pulmonary fibrosis ,Immunology ,Pulmonary fibrosis ,medicine ,Humans ,Telomerase reverse transcriptase ,Gene ,Exome - Abstract
The occurrence of pulmonary fibrosis in numerous individuals from the same family suggests a genetic cause for the disease. During the last 10 years, mutations involving proteins from the telomerase complex and from the surfactant system have been identified in association with pulmonary fibrosis. Mutations of TERT, the coding gene for the telomerase reverse transcriptase, are the most frequently identified mutations and are present in 15% of cases of familial pulmonary fibrosis. Other mutations (TERC, surfactant proteins genes) are only rarely evidenced in adults. Patients with mutations involving the telomerase complex may present with pulmonary fibrosis, hematologic, cutaneous or liver diseases. Other genetic variations associated with pulmonary fibrosis such as a polymorphism in the promoter of MUC5B or a polymorphism in TERT have been recently described, and could be considered to be part of a polygenic transmission. Evidence for mutations associated with the development of pulmonary fibrosis raises numerous clinical questions from establishing a diagnosis, providing counselling to deciding on therapy, and requires specific studies. From a pathophysiological point of view, the function of the genes highlights the central role of alveolar epithelium and aging in fibrogenesis.
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- 2015
91. Mutation in human
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Yvette Y, Yien, Sarah, Ducamp, Lisa N, van der Vorm, Julia R, Kardon, Hana, Manceau, Caroline, Kannengiesser, Hector A, Bergonia, Martin D, Kafina, Zoubida, Karim, Laurent, Gouya, Tania A, Baker, Hervé, Puy, John D, Phillips, Gaël, Nicolas, and Barry H, Paw
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Male ,Adolescent ,Amino Acid Substitution ,PNAS Plus ,Porphyria, Erythropoietic ,Enzyme Stability ,Mutation, Missense ,Humans ,Protoporphyrins ,Female ,Endopeptidase Clp ,5-Aminolevulinate Synthetase - Abstract
Although heme synthesis is ubiquitous, specific regulatory mechanisms couple heme production to cellular demand and environmental conditions. The importance of these regulatory mechanisms is highlighted by clinical variability in porphyrias caused by loss-of-function mutations in heme synthesis enzymes. Heme synthesis is also controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in both heme-dependent degradation of δ-aminolevulinate synthase (ALAS) and ALAS activation. This study reports a human familial mutation in CLPX that contributes to erythropoietic protoporphyria (EPP) by partially inactivating CLPX. Reduced CLPX activity increases ALAS post-translational stability, causing pathological accumulation of protoporphyrin IX (PPIX) in human patients. Our results thus identify an additional gene that promotes PPIX overproduction and EPP and highlight the complex gene network contributing to disorders of heme metabolism.
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- 2017
92. Mutation in human CLPX elevates levels of δ- aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria
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Sarah Ducamp, Yvette Y. Yien, Laurent Gouya, Hector A. Bergonia, Martin D. Kafina, Hana Manceau, Julia R. Kardon, Caroline Kannengiesser, Lisa N. van der Vorm, Gaël Nicolas, Hervé Puy, Barry H. Paw, John D. Phillips, Zoubida Karim, Tania A. Baker, Division of Hematology [Boston, MA, USA], Brigham and Women's Hospital [Boston]-Harvard Medical School [Boston] (HMS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Français des Porphyries [AP-HP Hôpital Louis Mourier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biology [MIT Cambridge, USA], Massachusetts Institute of Technology (MIT), Howard Hughes Medical Institute [Cambridge, MA, USA], Département de Génétique [AP-HP Hôpital Bichat] (Hôpitaux Universitaires Paris Nord Val de Seine - HUPNVS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Nord Val de Seine (HUPNVS), Division of Hematology [Salt Lake City, UT, USA], University of Utah School of Medicine [Salt Lake City], Division of Hematology-Oncology [Boston, MA, USA] (Boston Children’s Hospital), Harvard Medical School [Boston] (HMS), Department of Pediatric Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Dana-Farber Cancer Institute [Boston], This work was supported by grants from The Netherlands Society for Biochemistry and Molecular Biology (Nora Baart Foundation), the RadboudUMC Master thesis prize, the Radboud University Master thesis award, and the Dutch Stomach Liver Bowel Foundation (L.N.v.d.V.), the Public Health and Consumer Protection Directorate Public Health Executive Agency of the European Commission, ANR-GIS Maladies Rares Grant ANR07-MRAR-008-01, and the Laboratoire d’Excellence Gr-Ex, reference ANR-11-LABX-0051 (to H.P., L.G., G.N., Z.K., and C.K.). The labex GR-Ex is funded by the program 'Investissements d’Avenir' of the French National Research Agency, reference ANR-11-IDEX-0005-02. Additional support was provided by the Howard Hughes Medical Institute (T.A.B.) and National Institutes of Health Grants F32 DK098866 (to Y.Y.Y.), K01 DK106156 (to Y.Y.Y.), F32 DK095726 (to J.R.K.), R01 GM049224 (to T.A.B.), R01 DK020503 (to J.D.P.), U54 DK083909 (to J.D.P.), R01 DK070838 (to B.H.P.), and P01 HL032262 (to B.H.P.). J.R.K. and T.A.B. are employees of the Howard Hughes Medical Institute., ANR-07-MRAR-0008,EPP-HMA,Identification des gènes et des mécanismes physio-pathologiques impliqués dans une nouvelle forme de protoporphyrie érythropoïétique et dans des cas rares d'anémie microcytaire hypochrome.(2007), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), NICOLAS, Gaël, Maladies rares - Identification des gènes et des mécanismes physio-pathologiques impliqués dans une nouvelle forme de protoporphyrie érythropoïétique et dans des cas rares d'anémie microcytaire hypochrome. - - EPP-HMA2007 - ANR-07-MRAR-0008 - MRAR - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston]
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[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,0301 basic medicine ,protein unfoldases ,[SDV]Life Sciences [q-bio] ,ATPase ,Mutant ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,medicine.disease_cause ,porphyria ,03 medical and health sciences ,chemistry.chemical_compound ,ALAS ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Heme ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Mutation ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Multidisciplinary ,Protoporphyrin IX ,ATP synthase ,heme biosynthesis ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Porphyria ,chemistry ,Biochemistry ,biology.protein ,Erythropoietic protoporphyria ,AAA+ ATPase ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism.
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- 2017
93. SFTPA mutations in interstitial lung disease (ILD) and lung cancer
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Nadia Nathan, Carine Gomez, Serge Amselem, Diane Bouvry, Violaine Giraud, Bruno Crestani, Marie Legendre, Hilario Nunes, Jean-Charles Dalphin, Gregoire Prevost, Emilie Filhol-Blin, Caroline Kannengiesser, Martine Reynaud-Gaubert, Paul De Vuyst, Xavier Jeunemaitre, Philippe Duquesnoy, Laurent Gouya, Juliette Albuisson, Bruno Copin, Florence Dastot-Le Moal, Valérie Nau, Annick Clement, Raphael Borie, and Clément Picard
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education.field_of_study ,biology ,business.industry ,Population ,Interstitial lung disease ,respiratory system ,Lung injury ,ABCA3 ,medicine.disease ,behavioral disciplines and activities ,respiratory tract diseases ,Surfactant protein A ,SFTPA2 ,Cancer research ,medicine ,biology.protein ,education ,Lung cancer ,business ,Surfactant homeostasis - Abstract
Background: The surfactant protein A (SP)-A is a collectin implicated in surfactant homeostasis, local alveolar immune response, and epithelial repair after lung injury. SP-A is encoded by the SFTPA1 and SFTPA2 genes. The aim of this study was to search for mutations in SFTPA1 and SFTPA2 in adult patients with ILD. Methods: All SFTPA1 and SFTPA2 exons and flanking intronic sequences were analyzed in a large prospective study population of 160 apparently unrelated ILD patients with no telomerase, SFTPC or ABCA3 mutations. Results: 86 patients were diagnosed with a familial form of ILD, of whom 20 presented an association with a familial lung cancer. 63 patients were Discussion and conclusion: Altered SP-A expression may contribute to ILD pathophysiology. Data reported herein indicate that patients with ILD and a personal or familial lung cancer, and/or
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- 2017
94. Non syndromic childhood onset congenital sideroblastic anemia: A report of 13 patients identified with an ALAS2 or SLC25A38 mutation
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Thierry Leblanc, Hana Manceau, Fanny Fouyssac, J.F. Guichard, Nadja Jäkel, Patrick Lutz, Jean-Pierre Vannier, Cyrielle Fouquet, Fabienne Toutain, Mohamed Touati, Christiane Vermylen, Yves Perel, Marie-Amelyne Le Rouzic, Karim Maloum, Caroline Kannengiesser, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Université de Bordeaux (UB), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique Hématologique, Clinique Universitaire Saint-Luc, de Duve Institute, UCL, Médecine Interne-Pathologie Vasculaire - Immunologie Clinique, Hôpital Sainte Blandine, Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pontchaillou [Rennes], Hôpital Civil, Hopital Civil, Service d'hématologie pédiatrique et oncologie, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), California Institute of Technology (CALTECH)-NASA, 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 Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN)
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Pathology ,medicine.medical_specialty ,Pediatrics ,Iron Overload ,[SDV]Life Sciences [q-bio] ,Mitochondrial Membrane Transport Proteins ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Humans ,Chelation therapy ,Child ,Adverse effect ,Molecular Biology ,Congenital sideroblastic anemia ,ComputingMilieux_MISCELLANEOUS ,Retrospective Studies ,business.industry ,Cell Biology ,Hematology ,ALAS2 ,Anemia, Sideroblastic ,3. Good health ,Phenotype ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Molecular Medicine ,business ,Non syndromic ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,5-Aminolevulinate Synthetase ,030215 immunology - Abstract
The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.
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- 2017
95. AB0007 Shared genetic predisposition in rheumatoid arthritis–interstitial lung disease and familial pulmonary fibrosis
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Serge Amselem, Marie-Christophe Boissier, Catherine Boileau, Benoit Wallaert, Aurélien Justet, Gabriel Thabut, Baptiste Coustet, A Clément, Bruno Crestani, Martin Soubrier, Yannick Allanore, Vincent Cottin, S. Ottaviani, Nadia Nathan, Christelle Ménard, Olivier Sand, Steven Gazal, Hilario Nunes, Lidwine Wemeau-Stervinou, H. Lioté, Isabelle Callebaut, Philippe Dieudé, Pierre-Antoine Juge, Marie-Pierre Debray, P. Richette, R.M. Flipo, Patrick Revy, Dominique Valeyre, Dlm Florence, S. Marchand-Adam, J. Sibilia, T. Schaeverbeke, Aline Frazier, Christophe Richez, Caroline Kannengiesser, Raphael Borie, Claire Dromer, and N. Saidenberg
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,Mutation ,business.industry ,Interstitial lung disease ,Odds ratio ,respiratory system ,medicine.disease ,medicine.disease_cause ,respiratory tract diseases ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Usual interstitial pneumonia ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Internal medicine ,Pulmonary fibrosis ,medicine ,Genetic predisposition ,business - Abstract
Background Despite its high prevalence and mortality, little is known about the pathogenesis of RA–associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA–ILD frequently share the usual interstitial pneumonia pattern and common environmental risk factors, we hypothesized that the two diseases may share additional risk factors including FPF-linked genes. Objectives Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. Methods We used whole-exome sequencing (WES) followed by restricted analysis of a discrete number of FPF-linked genes and performed a Burden test to assess the excess number of mutations in RA–ILD patients compared to controls. Results Among the 101 RA–ILD patients included, 12 (11.9%) had 13 WESidentified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA–ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations for RA–ILD patients (p=9.45’10-4, odds ratio [OR] 3.17 95% CI 1.53 – 6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87x10-2). Conclusions Our results support the contribution of FPF-linked genes to RA–ILD susceptibility. Disclosure of Interest None declared
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- 2017
96. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis
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Steven Gazal, Hilario Nunes, Jean Sibilia, Christelle Ménard, Aurélien Justet, Philippe Dieudé, Isabelle Callebaut, Amélie Bonnefond, Martin Soubrier, Patrick Revy, Catherine Boileau, Pierre-Antoine Juge, Thierry Schaeverbeke, Aline Frazier, Nathalie Saidenberg, Sébastien Ottaviani, Nadia Nathan, Bruno Crestani, Christophe Béroud, Baptiste Coustet, Vincent Cottin, Lidwine Wemeau-Stervinou, Jean-Pierre Desvignes, Marie-Christophe Boissier, Florence Dastot-Le Moal, Serge Amselem, Philippe Froguel, Yannick Allanore, Annick Clement, Olivier Sand, Gabriel Thabut, Marie-Pierre Debray, Pascal Richette, Caroline Kannengiesser, Benoit Wallaert, Christophe Richez, Dominique Valeyre, Sylvain Marchand-Adam, Huguette Lioté, Nicolas Leulliot, René-Marc Flipo, Raphael Borie, Claire Dromer, David Salgado, Service de Rhumathologie, Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Service de Pneumologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), UMR 1152, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), UMR 1149, Centre de Recherches sur l'Inflammation, Ecologie et Ecophysiologie Forestières [devient SILVA en 2018] (EEF), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Plateforme de génomique constitutionnelle, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie et Immuno-Allergologie [CHU LIlle], Pole Cardio-vasculaire et pulmonaire [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Service de Radiologie, Hospices Civils de Lyon (HCL), UMR 1100, Université Francois Rabelais [Tours], Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Rhumatologie, CH Belfort-Montbéliard, UMR 5164, Immuno ConcEpT Lab, Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD [France-Ouest]), Muséum national d'Histoire naturelle (MNHN), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université de Lille, Droit et Santé, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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), 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), UMR 1132, Service de Rhumatologie, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Department of Genomics of Common Diseases, Imperial College London, Service Rhumatologie A, Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 Imagerie, service de Rhumatologie, Centre Hospitalier Universitaire de Lille (CHU de Lille), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Rhumatologie, Hôpital La Rabta [Tunis], FMTS, CRHI, Laboratoire Immunologie Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA), Fédération Hospitalo-Universitaire OMICARE, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Maladie Pulmonaires Rares, Hôpital Louis Pradel [CHU - HCL], UMR U1125 Service rhumatologie, service de rhumatologie, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Hôpital Avicenne [AP-HP], service de génétique, Societe Francaise de Rhumatologie, Club Rhumatismes Inflammation, la Chancellerie des Universites de Paris (legs Poix), Sorbonne Paris Cite (FPI-SPC Program), Agence Nationale de la Recherche ANR-10-LABX-46 ANR-10-EQPX-07-01 ANR-14-CE10-0006 ANR-10-INBS-09, France Genomique National Infrastructure, Pfizer, Chugai, Centre de Resources Biologiques Hopital Bichat Paris France, ANR-14-CE10-0006,GENEXGERTEL,Rôles génomiques et extragénomiques de RTEL1(2014), Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Université Paris Diderot (Paris 7), Université Sorbonne Paris Cité ( USPC ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Saint-Etienne, UMR 1137, Fac Sci, 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 National de la Recherche Scientifique ( CNRS ), Service de Pneumologie et Immuno-Allergologie, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hospices Civils de Lyon ( HCL ), Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie (Paris 6), Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Sorbonne Universités, Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche pour le Développement ( IRD [France-Ouest] ), Muséum National d’Histoire Naturelle ( MNHN ), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Droit et Santé (Lille 2) ( UDSL ), European Genomic Institute for Diabetes ( EGID ), 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 ), Hôpital Lariboisière, Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre Hospitalier Universitaire de Lille ( CHU de Lille ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hôpital La Rabta [Tunis), Université de Strasbourg ( UNISTRA ), Rétrovirus et Pathologie Comparée ( RPC ), Institut National de la Recherche Agronomique ( INRA ) -École pratique des hautes études ( EPHE ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon ( ENVL ), Département Génétique, Institut de l'Elevage, Centre Reference Maladies Respiratoires Rares, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Centre Hospitalier Universitaire de Clermont-Ferrand, Unité de Nutrition Humaine - Clermont Auvergne ( UNH ), Université Clermont Auvergne ( UCA ) -Institut national de la recherche agronomique [Auvergne/Rhône-Alpes] ( INRA Auvergne/Rhône-Alpes ), Centre de Recherche en Nutrition Humaine d'Auvergne ( CRNH d'Auvergne ), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris ( AP-HP ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Institut de l'élevage (IDELE), ProdInra, Archive Ouverte, Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [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)-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), Service de génétique et embryologie médicales [CHU Trousseau], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), European Genomic Institute for Diabetes [Lille] (EGID), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris (AP-HP), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and 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)
- Subjects
Male ,Pathology ,medicine.disease_cause ,Arthritis, Rheumatoid ,0302 clinical medicine ,Risk Factors ,Pulmonary fibrosis ,Exome ,Telomerase ,Exome sequencing ,Mutation ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Interstitial lung disease ,Middle Aged ,3. Good health ,Europe ,Polyarthrite rhumatoïde ,maladie pulmonaire ,Phenotype ,Rheumatoid arthritis ,Female ,Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Heterozygote ,fibrose pulmonaire ,03 medical and health sciences ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,respiratory system diseases ,Genetic Association Studies ,Aged ,030203 arthritis & rheumatology ,pulmonary fibrosis ,business.industry ,Case-control study ,DNA Helicases ,Sequence Analysis, DNA ,medicine.disease ,030228 respiratory system ,Case-Control Studies ,Immunology ,business ,Lung Diseases, Interstitial ,Software ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.
- Published
- 2017
97. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)
- Author
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Philip Connor, Daniel H. Wiseman, Stephen M. Hughes, Martin Holcik, Laura Marques, Denise Bonney, Michael T. Geraghty, Ronald M. Laxer, Pranesh Chakraborty, Colin Powell, Alexis A. Thompson, Isabelle Thuret, Dean R. Campagna, Matthew M. Heeney, Turaya Naas, Alison May, Victoria Bordon, Caterina P. Minniti, Adam D. Rudner, Robert J. Klaassen, Patricia-Jane Giardina, Ashley Lau, Sylvia S. Bottomley, Robert Wynn, John Moppett, Klaus Schmitz-Abe, Kyriacos Markianos, Caroline Kannengiesser, Erin K. Kennedy, Mark D. Fleming, Hapsatou Mamady, Stephen Jolles, Danielle Durie, Paul B.M. Joyce, and Anoop K. Sendamarai
- Subjects
Fever ,Developmental Disabilities ,Immunology ,Biology ,Mitochondrion ,medicine.disease_cause ,Biochemistry ,Red Cells, Iron, and Erythropoiesis ,Pleiotropy ,medicine ,Humans ,Allele ,Gene ,Alleles ,Immunodeficiency ,Genetics ,Mutation ,Immunologic Deficiency Syndromes ,Genetic Diseases, X-Linked ,RNA Nucleotidyltransferases ,Cell Biology ,Hematology ,medicine.disease ,Phenotype ,Anemia, Sideroblastic ,HEK293 Cells ,Biogenesis - Abstract
Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.
- Published
- 2014
98. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis
- Author
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Lidwine Wemeau-Stervinou, Julie Mankikian, Patrick Revy, Martine Reynaud Gaubert, Christelle Ménard, Jacques Cadranel, Dominique Israel-Biet, Hervé Mal, Grégoire Prévot, Bruno Crestani, Caroline Kannengiesser, Hilario Nunes, Abdellatif Tazi, Dominique Valeyre, Gabriel Thabut, Vincent Cottin, Marion Reocreux, Raphael Borie, Clément Picard, Stéphane Jouneau, Bernard Grandchamp, Anne Bergeron Lafaurie, Laure Tabèze, Sylvain Marchand-Adam, Jean-François Cordier, Jean-Marc Naccache, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie A, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de compétence des maladies pulmonaires rares, Service de pneumologie B, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de médecine nucléaire [Bobigny], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Service de pneumologie [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-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), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [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), Theranoscan, Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'oncologie médicale (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Pneumologie, Paris, Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), CHU Marseille, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service des maladies respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Hôpital Bichat - Claude Bernard, OMMIC S.A.S., OMMIC SAS, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling), LabEx Inflamex, Service de pneumologie A, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Bichat, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), OMMIC, Chard-Hutchinson, Xavier, Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Centre de compétence des maladies pulmonaires rares, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Hospices Civils de Lyon ( HCL ), Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU, Hôpital Larrey, Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microenvironnement et cancer ( MiCa ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Claude Bernard Lyon 1 ( UCBL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Bichat, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Macrocytosis ,030204 cardiovascular system & hematology ,Gene mutation ,medicine.disease_cause ,Gastroenterology ,[ SDV.EE ] Life Sciences [q-bio]/Ecology, environment ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Cause of Death ,Pulmonary fibrosis ,Telomerase rna ,medicine ,Humans ,Interstitial pneumonia ,Telomerase reverse transcriptase ,Telomerase ,Aged ,Retrospective Studies ,Aged, 80 and over ,[SDV.EE]Life Sciences [q-bio]/Ecology, environment ,Mutation ,[ SDV ] Life Sciences [q-bio] ,business.industry ,Middle Aged ,Telomere ,medicine.disease ,Survival Analysis ,Idiopathic Pulmonary Fibrosis ,3. Good health ,[SDV] Life Sciences [q-bio] ,[SDV.EE] Life Sciences [q-bio]/Ecology, environment ,Logistic Models ,030228 respiratory system ,Multivariate Analysis ,RNA ,Female ,France ,business - Abstract
Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007–2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40–60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.
- Published
- 2016
99. The genetics of interstitial lung diseases
- Author
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Clairelyne Dupin, Pierre Le Guen, Mada Ghanem, Bruno Crestani, Caroline Kannengiesser, Camille Taillé, Philippe Dieudé, and Raphael Borie
- Subjects
Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Clinical manifestation ,Risk Assessment ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Fibrosis ,Animals ,Humans ,Medicine ,Lung transplantation ,Genetic Predisposition to Disease ,Lung volumes ,030212 general & internal medicine ,Genetic risk ,Lung ,lcsh:RC705-779 ,business.industry ,Genetic variants ,Genetic Variation ,lcsh:Diseases of the respiratory system ,respiratory system ,medicine.disease ,respiratory tract diseases ,body regions ,Phenotype ,Treatment Outcome ,medicine.anatomical_structure ,030228 respiratory system ,Respiratory failure ,Lung Diseases, Interstitial ,business ,Lung Transplantation - Abstract
Interstitial lung diseases (ILDs) are a set of heterogeneous lung diseases characterised by inflammation and, in some cases, fibrosis. These lung conditions lead to dyspnoea, cough, abnormalities in gas exchange, restrictive physiology (characterised by decreased lung volumes), hypoxaemia and, if progressive, respiratory failure. In some cases, ILDs can be caused by systemic diseases or environmental exposures. The ability to treat or cure these ILDs varies based on the subtype and in many cases lung transplantation remains the only curative therapy. There is a growing body of evidence that both common and rare genetic variants contribute to the development and clinical manifestation of many of the ILDs. Here, we review the current understanding of genetic risk and ILD.
- Published
- 2019
100. Fibrose pulmonaire dans un contexte de téloméropathie avec mutation TERC
- Author
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F. Serradj, Caroline Kannengiesser, A. Mokhtari, S. Lellou, K. Boussouf, Raphael Borie, and F. Sicre De Fontbrune
- Subjects
Pulmonary and Respiratory Medicine - Abstract
Introduction Des mutations heterozygotes du gene codant pour le composant ARN de la telomerase (TERC) sont retrouvees dans 3 % des fibroses pulmonaires familiales et sont encore plus rares dans les fibroses pulmonaires idiopathiques sporadiques. Methodes Nous rapportons le cas d’un patient (pt) âge de 32 ans, admis en pneumologie pour pneumopathie interstitielle diffuse (PID) chronique fibrosante au stade d’insuffisance respiratoire. Hemopathie chez le pere et la sœur. Quatre ans auparavant, apparition de toux seche, dyspnee d’effort d’aggravation progressive avec deterioration plus rapide durant la derniere annee ecoulee. A l’admission : dyspnee MMRC4, hippocratisme digital, râles crepitants aux 2 champs pulmonaires, canitie precoce. TDM thoracique : aspects de pneumopathie interstitielle commune aux bases et de fibro-elastose pleuroparenchymateuse aux sommets. NFS : thrombopenie, leucopenie. Biopsie medullaire : hypoplasie medullaire. Mutation somatique V617F de JAK2(+). Anticorps anti-Pm-SCL75(+), anti-SRP(+), anti-PL12(+), anti-cardiolipine(+), anti-BPI(+). Echodoppler hepatique : syndrome d’hypertension portale. NGS telomeropathie : mutation constitutionnelle heterozygote de TERC. Pt traite par Danazol. Il a interrompu son traitement apres 1 mois a cause de tachycardie mal toleree. L’evolution etait pejorative avec deces apres 3 mois. Resultats Les aspects scanographiques et les manifestations extra-pulmonaires de ce pt temoignent du polymorphisme radio-clinique qui caracterise les telomeropathies. Afin d’eviter le retard diagnostique qui a ete observe chez ce pt, une analyse genetique devrait etre proposee dans des situations specifiques incluant l’association d’une PID a une histoire personnelle ou familiale evocatrice de telomeropathie. L’evolution pejorative de ce pt concorde avec les donnees de la litterature. En effet, la survie chez les pts porteurs de mutations du complexe telomerase semble plus courte avec un declin de la capacite vitale forcee plus important. Des donnees prospectives et retrospectives recentes sont en faveur d’un benefice du Danazol sur les atteintes pulmonaire et hematologique ; chez notre pt la courte duree de prise du medicament ne nous permet pas d’evaluer la reponse therapeutique. Conclusion Les PID dans un contexte evocateur de telomeropathies soulevent de nombreux problemes specifiques, notamment en ce qui concerne le diagnostic genetique, les options therapeutiques (antifibrotiques, Danazol, greffes pulmonaires ou medullaires) et le conseil genetique, ce qui rend primordial une prise en charge multidisciplinaire.
- Published
- 2019
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