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2. Prenatal diagnosis of SLC25A24 Fontaine progeroid syndrome: description of the fetal phenotype, genotype and detection of parental mosaicism.

Author

Pannier, Emmanuelle, Sekri, Abel, Roux, Nathalie, Vasiljevic, Alexandre, El Khattabi, Laïla, Chatron, Nicolas, Grotto, Sarah, Menzella, Delphine, Grangé, Gilles, Thébault, Florent, Massardier, Jérôme, Fourrage, Cécile, Lohmann, Laurence, Tsatsaris, Vassilis, Putoux, Audrey, Boutaud, Lucile, and Attié‐Bitach, Tania

Abstract

Background: Fontaine progeroid syndrome (FPS, OMIM 612289) is a recently identified genetic disorder stemming from pathogenic variants in the SLC25A24 gene, encoding a mitochondrial carrier protein. It encompasses Gorlin–Chaudry–Moss syndrome and Fontaine–Farriaux syndrome, primarily manifesting as craniosynostosis with brachycephaly, distinctive dysmorphic facial features, hypertrichosis, severe prenatal and postnatal growth restriction, limb shortening, and early aging with characteristic skin changes, phalangeal anomalies, and genital malformations. Cases: All known occurrences of FPS have been postnatally observed until now. Here, we present the first two prenatal cases identified during the second trimester of pregnancy. While affirming the presence of most postnatal abnormalities in prenatal cases, we note the absence of a progeroid appearance in young fetuses. Notably, our reports introduce new phenotypic features like encephalocele and nephromegaly, which were previously unseen postnatally. Moreover, paternal SLC25A24 mosaicism was detected in one case. Conclusions: We present the initial two fetal instances of FPS, complemented by thorough phenotypic and genetic assessments. Our findings expand the phenotypical spectrum of FPS, unveiling new fetal phenotypic characteristics. Furthermore, one case underscores a potential novel inheritance pattern in this disorder. Lastly, our observations emphasize the efficacy of exome/genome sequencing in both prenatal and postmortem diagnosis of rare polymalformative syndromes with a normal karyotype and array‐based comparative genomic hybridization (CGH). [ABSTRACT FROM AUTHOR]

Published
2024
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3. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Author

Hadjadj, Jérôme, Aladjidi, Nathalie, Fernandes, Helder, Leverger, Guy, Magérus-Chatinet, Aude, Mazerolles, Fabienne, Stolzenberg, Marie-Claude, Jacques, Sidonie, Picard, Capucine, Rosain, Jérémie, Fourrage, Cécile, Hanein, Sylvain, Zarhrate, Mohammed, Pasquet, Marlène, Abou Chahla, Wadih, Barlogis, Vincent, Bertrand, Yves, Pellier, Isabelle, Colomb Bottollier, Elodie, Fouyssac, Fanny, Blouin, Pascale, Thomas, Caroline, Cheikh, Nathalie, Dore, Eric, Pondarre, Corinne, Plantaz, Dominique, Jeziorski, Eric, Millot, Frédéric, Garcelon, Nicolas, Ducassou, Stéphane, Perel, Yves, Leblanc, Thierry, Neven, Bénédicte, Fischer, Alain, and Rieux-Laucat, Frédéric

Published
2019
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4. The genome of the jellyfish Clytia hemisphaerica and the evolution of the cnidarian life-cycle

Author

Leclère, Lucas, Horin, Coralie, Chevalier, Sandra, Lapébie, Pascal, Dru, Philippe, Peron, Sophie, Jager, Muriel, Condamine, Thomas, Pottin, Karen, Romano, Séverine, Steger, Julia, Sinigaglia, Chiara, Barreau, Carine, Quiroga Artigas, Gonzalo, Ruggiero, Antonella, Fourrage, Cécile, Kraus, Johanna E. M., Poulain, Julie, Aury, Jean-Marc, Wincker, Patrick, Quéinnec, Eric, Technau, Ulrich, Manuel, Michaël, Momose, Tsuyoshi, Houliston, Evelyn, and Copley, Richard R.

Published
2019
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5. Diagnosis of Menke‐Hennekam syndrome by prenatal whole exome sequencing and review of prenatal signs.

Author

Cogan, Guillaume, Bourgon, Nicolas, Borghese, Roxana, Julien, Emmanuel, Jaquette, Aurélia, Stos, Bertrand, Achaiaa, Amale, Chuon, Sophie, Nitschke, Patrick, Fourrage, Cécile, Stirnemann, Julien, Boutaud, Lucile, and Attie‐Bitach, Tania

Subjects
GROWTH disorders, HEARING disorders, ABORTION, SHORT stature, FACIAL abnormalities, AGENESIS of corpus callosum
Abstract

Introduction: CREBBP truncating mutations and deletions are responsible for the well‐known Rubinstein‐Taybi syndrome. Recently, a new, distinct CREBBP‐linked syndrome has been described: missense mutations located at the 3′ end of exon 30 and the 5′ portion of exon 31 induce Menke‐Hennekam syndrome. Patients with this syndrome present a recognizable facial dysmorphism, intellectual disability of variable severity, microcephaly, short stature, autism, epilepsy, visual and hearing impairments, feeding problems, upper airway infections, scoliosis, and/or kyphosis. To date, all diagnoses were made postnatally. Method and Case Report: Trio‐whole exome sequencing (WES) was performed in a fetus showing increased nuchal translucency persistence and aorta abnormalities at 28 weeks of gestation (WG). Results: WES revealed a CREBBP de novo missense mutation (c.5602C>T; p.Arg1868Trp) in exon 31, previously reported as the cause of Menke‐Hennekam syndrome. Termination of pregnancy was performed at 32 WG. We further reviewed the prenatal signs of Menke‐Hennekam syndrome already reported. Among the 35 patients reported and diagnosed postnatally up to this day, 15 presented recognizable prenatal signs, the most frequent being intra‐uterine growth retardation, brain, and cardiovascular anomalies. Conclusion: Menke‐Hennekam is a rare syndrome with unspecific, heterogeneous, and inconstant prenatal symptoms occurring most frequently with the c.5602C>T, p.(Arg1868Trp) mutation. Therefore, the prenatal diagnosis of Menke‐Hennekam syndrome is only possible by molecular investigation. Moreover, this case report and review reinforce the importance of performing prenatal WES when unspecific signs are present on imaging. [ABSTRACT FROM AUTHOR]

Published
2023
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6. Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract

Author

Heidet, Laurence, Morinière, Vincent, Henry, Charline, De Tomasi, Lara, Reilly, Madeline Louise, Humbert, Camille, Alibeu, Olivier, Fourrage, Cécile, Bole-Feysot, Christine, Nitschké, Patrick, Tores, Frédéric, Bras, Marc, Jeanpierre, Marc, Pietrement, Christine, Gaillard, Dominique, Gonzales, Marie, Novo, Robert, Schaefer, Elise, Roume, Joëlle, Martinovic, Jelena, Malan, Valérie, Salomon, Rémi, Saunier, Sophie, Antignac, Corinne, and Jeanpierre, Cécile

Published
2017
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7. Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study

Author

Philippot, Quentin, Kannengiesser, Caroline, Debray, Marie Pierre, Gauvain, Clément, Ba, Ibrahima, Vieri, Margherita, Gondouin, Anne, Naccache, Jean Marc, Reynaud-Gaubert, Martine, Uzunhan, Yurdagul, Bondue, Benjamin, Israël-Biet, Dominique, Dieudé, Philippe, Fourrage, Cécile, Lainey, Elodie, Manali, Effrosyne, Papiris, Spyridon, Wemeau, Lidwine, Hirschi, Sandrine, Mal, Hervé, Nunes, Hilario, Schlemmer, Frédéric, Blanchard, Elodie, Beier, Fabian, Cottin, Vincent, Crestani, Bruno, Borie, Raphael, Philippot, Quentin, Kannengiesser, Caroline, Debray, Marie Pierre, Gauvain, Clément, Ba, Ibrahima, Vieri, Margherita, Gondouin, Anne, Naccache, Jean Marc, Reynaud-Gaubert, Martine, Uzunhan, Yurdagul, Bondue, Benjamin, Israël-Biet, Dominique, Dieudé, Philippe, Fourrage, Cécile, Lainey, Elodie, Manali, Effrosyne, Papiris, Spyridon, Wemeau, Lidwine, Hirschi, Sandrine, Mal, Hervé, Nunes, Hilario, Schlemmer, Frédéric, Blanchard, Elodie, Beier, Fabian, Cottin, Vincent, Crestani, Bruno, and Borie, Raphael

Abstract

Background and objective: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations. Methods: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network. Results: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range −363 to −148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation. Conclusion: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2022

8. Novel CDK10 variants with multicystic dysplastic kidney, left ventricular non‐compaction, and a solitary median maxillary central incisor

Author

Darcha, Claude, primary, Laffargue, Fanny, additional, Boutaud, Lucile, additional, Gallot, Denis, additional, Dauphin, Claire, additional, Garcier, Jean Marc, additional, Achaiaa, Amale, additional, Nitschke, Patrick, additional, Fourrage, Cécile, additional, Goumy, Carole, additional, and Attie‐Bitach, Tania, additional

Published
2021
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9. High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis

Author

Stoupa, Athanasia, primary, Al Hage Chehade, Ghada, additional, Chaabane, Rim, additional, Kariyawasam, Dulanjalee, additional, Szinnai, Gabor, additional, Hanein, Sylvain, additional, Bole-Feysot, Christine, additional, Fourrage, Cécile, additional, Nitschke, Patrick, additional, Thalassinos, Caroline, additional, Pinto, Graziella, additional, Mnif, Mouna, additional, Baron, Sabine, additional, De Kerdanet, Marc, additional, Reynaud, Rachel, additional, Barat, Pascal, additional, Hachicha, Mongia, additional, Belguith, Neila, additional, Polak, Michel, additional, and Carré, Aurore, additional

Published
2021
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10. Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic RPGRIP1 Pathologic Variant in the French Leber Congenital Amaurosis Cohort

Author

Perrault, Isabelle, primary, Hanein, Sylvain, additional, Gérard, Xavier, additional, Mounguengue, Nelson, additional, Bouyakoub, Ryme, additional, Zarhrate, Mohammed, additional, Fourrage, Cécile, additional, Jabot-Hanin, Fabienne, additional, Bocquet, Béatrice, additional, Meunier, Isabelle, additional, Zanlonghi, Xavier, additional, Kaplan, Josseline, additional, and Rozet, Jean-Michel, additional

Published
2021
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11. Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Author

Fusaro, Mathieu, primary, Rosain, Jérémie, additional, Grandin, Virginie, additional, Lambert, Nathalie, additional, Hanein, Sylvain, additional, Fourrage, Cécile, additional, Renaud, Nicholas, additional, Gil, Marine, additional, Chevalier, Samuel, additional, Chahla, Wadih Abou, additional, Bader-Meunier, Brigitte, additional, Barlogis, Vincent, additional, Blanche, Stéphane, additional, Boutboul, David, additional, Castelle, Martin, additional, Comont, Thibault, additional, Diana, Jean-Sébastien, additional, Fieschi, Claire, additional, Galicier, Lionel, additional, Hermine, Olivier, additional, Lefèvre-Utile, Alain, additional, Malphettes, Marion, additional, Merlin, Etienne, additional, Oksenhendler, Eric, additional, Pasquet, Marlène, additional, Suarez, Felipe, additional, André, Isabelle, additional, Béziat, Vivien, additional, De Saint Basile, Geneviève, additional, De Villartay, Jean-Pierre, additional, Kracker, Sven, additional, Lagresle-Peyrou, Chantal, additional, Latour, Sylvain, additional, Rieux-Laucat, Frédéric, additional, Mahlaoui, Nizar, additional, Bole, Christine, additional, Nitschke, Patrick, additional, Hulier-Ammar, Elisabeth, additional, Fischer, Alain, additional, Moshous, Despina, additional, Neven, Bénédicte, additional, Alcais, Alexandre, additional, Vogt, Guillaume, additional, Bustamante, Jacinta, additional, and Picard, Capucine, additional

Published
2021
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12. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Author

Charbit-Henrion, Fabienne, primary, Parlato, Marianna, additional, Hanein, Sylvain, additional, Duclaux-Loras, Rémi, additional, Nowak, Jan, additional, Begue, Bernadette, additional, Rakotobe, Sabine, additional, Bruneau, Julie, additional, Fourrage, Cécile, additional, Alibeu, Olivier, additional, Rieux-Laucat, Frédéric, additional, Lévy, Eva, additional, Stolzenberg, Marie-Claude, additional, Mazerolles, Fabienne, additional, Latour, Sylvain, additional, Lenoir, Christelle, additional, Fischer, Alain, additional, Picard, Capucine, additional, Aloi, Marina, additional, Dias, Jorge Amil, additional, Hariz, Mongi Ben, additional, Bourrier, Anne, additional, Breuer, Christian, additional, Breton, Anne, additional, Bronsky, Jiri, additional, Buderus, Stephan, additional, Cananzi, Mara, additional, Coopman, Stéphanie, additional, Crémilleux, Clara, additional, Dabadie, Alain, additional, Dumant-Forest, Clémentine, additional, Gurkan, Odul Egritas, additional, Fabre, Alexandre, additional, Fischer, Aude, additional, Diaz, Marta German, additional, Gonzalez-Lama, Yago, additional, Goulet, Olivier, additional, Guariso, Graziella, additional, Gurcan, Neslihan, additional, Homan, Matjaz, additional, Hugot, Jean-Pierre, additional, Jeziorski, Eric, additional, Karanika, Evi, additional, Lachaux, Alain, additional, Lewindon, Peter, additional, Lima, Rosa, additional, Magro, Fernando, additional, Major, Janos, additional, Malamut, Georgia, additional, Mas, Emmanuel, additional, Mattyus, Istvan, additional, Mearin, Luisa M, additional, Melek, Jan, additional, Navas-Lopez, Victor Manuel, additional, Paerregaard, Anders, additional, Pelatan, Cecile, additional, Pigneur, Bénédicte, additional, Pais, Isabel Pinto, additional, Rebeuh, Julie, additional, Romano, Claudio, additional, Siala, Nadia, additional, Strisciuglio, Caterina, additional, Tempia-Caliera, Michela, additional, Tounian, Patrick, additional, Turner, Dan, additional, Urbonas, Vaidotas, additional, Willot, Stéphanie, additional, Ruemmele, Frank M, additional, and Cerf-Bensussan, Nadine, additional

Published
2020
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13. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal–Hreidarsson syndrome

Author

Benyelles, Maname, primary, O’Donohue, Marie-Françoise, primary, Kermasson, Laëtitia, primary, Lainey, Elodie, primary, Borie, Raphael, primary, Lagresle-Peyrou, Chantal, primary, Nunes, Hilario, primary, Cazelles, Clarisse, primary, Fourrage, Cécile, primary, Ollivier, Emmanuelle, primary, Marcais, Ambroise, primary, Gamez, Anne-Sophie, primary, Morice-Picard, Fanny, primary, Caillaud, Denis, primary, Pottier, Nicolas, primary, Ménard, Christelle, primary, Ba, Ibrahima, primary, Fernandes, Alicia, primary, Crestani, Bruno, primary, de Villartay, Jean-Pierre, primary, Gleizes, Pierre-Emmanuel, primary, Callebaut, Isabelle, primary, Kannengiesser, Caroline, primary, and Revy, Patrick, primary

Published
2020
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14. Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: A multicentre study

Author

Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Remi, Nowak, Jan, Bègue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Amil Dias, Jorge, Ben Hariz, Mongi, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronski, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Egritas Gurkan, Odul, Fabre, Alexandre, Fischer, Aude, German Diaz, Marta, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Janos, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Anders, Pelatan, Cecile, Pigneur, Bénédicte, Pinto Pais, Isabel, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidotas, Willot, Stéphanie, Ruemmele, Frank, Cerf-Bensussan, Nadine, Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Dias, Jorge Amil, Hariz, Mongi Ben, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronski, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Gurkan, Odul Egrita, Fabre, Alexandre, Fischer, Aude, Diaz, Marta German, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Jano, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa M, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Ander, Pelatan, Cecile, Pigneur, Bénédicte, Pais, Isabel Pinto, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidota, Willot, Stéphanie, Ruemmele, Frank M., Cerf-Bensussan, Nadine, Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - 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), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), GENIUS Group, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Gastroentérologie-Hépatologie et Nutrition Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Hospital de São João [Porto], Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), University of Messina, Department of Pediatrics, Centre Hospitalier Universitaire Mongi Slim [La Marsa], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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)-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 Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), CHU Le MAns, 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), 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 Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, paediatric, VEO-IBD, Adolescent, monogenic disorder, Gastroenterology, High-Throughput Nucleotide Sequencing, Infant, Genetics and molecular epidemiology, Inflammatory Bowel Diseases, monogenic disorders, Corrigenda, Cohort Studies, paediatrics, Predictive Value of Tests, Child, Preschool, TNGS, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Age of Onset, Child, Genetics and molecular epidemiology, monogenic disorders, paediatrics, TNGS, VEO-IBD, Gastroenterology, AcademicSubjects/MED00260
Abstract

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: Predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Published
2018

15. Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders

Author

Montaut, Solveig, Tranchant, Christine, Drouot, Nathalie, Rudolf, Gabrielle, Guissart, Claire, Tarabeux, Julien, Stemmelen, Tristan, Velt, Amandine, Fourrage, Cécile, Nitschké, Patrick, Gerard, Bénédicte, Mandel, Jean-Louis, Koenig, Michel, Chelly, Jamel, Anheim, Mathieu, Parkinson\textquoterights, French, Consortium, Movement Disorders, CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), 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), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - 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), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Bioinformatique [SFR Necker] (BIP-D), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Collège de France (CdF (institution)), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), 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 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)

Subjects
0301 basic medicine, Male, Myoclonus, Movement disorders, [SDV]Life Sciences [q-bio], Whole Exome Sequencing, 0302 clinical medicine, 80 and over, Prospective Studies, Age of Onset, Child, Exome sequencing, Original Investigation, Dystonia, Aged, 80 and over, Movement Disorders, High-Throughput Nucleotide Sequencing, Middle Aged, 3. Good health, Phenotype, Dystonic Disorders, Child, Preschool, Female, medicine.symptom, Sequence Analysis, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, Genotype, 03 medical and health sciences, Young Adult, Parkinsonian Disorders, Chorea, Internal medicine, Exome Sequencing, medicine, Humans, Preschool, Aged, Cerebellar ataxia, Genetic heterogeneity, business.industry, Infant, DNA, Sequence Analysis, DNA, medicine.disease, 030104 developmental biology, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Dystonic disorder
Abstract

International audience; Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016. Main Outcomes and Measures: Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders. Results: Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater. Conclusions and Relevance: High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

Published
2018

16. APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries.

Author

Gribouval, Olivier, Boyer, Olivia, Knebelmann, Bertrand, Karras, Alexandre, Dantal, Jacques, Fourrage, Cécile, Alibeu, Olivier, Hogan, Julien, Dossier, Claire, Tête, Marie Josèphe, Antignac, Corinne, and Servais, Aude

Subjects
FOCAL segmental glomerulosclerosis, NEPHROTIC syndrome, GLOMERULAR filtration rate, GENOTYPES, NUCLEOTIDE sequencing, GENEALOGY
Abstract

Background Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes. Methods In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes. Results The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02). Conclusions The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes. [ABSTRACT FROM AUTHOR]

Published
2019
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17. The genome of the jellyfish Clytia hemisphaerica and the evolution of the cnidarian life-cycle

Author

Leclère, Lucas, primary, Horin, Coralie, additional, Chevalier, Sandra, additional, Lapébie, Pascal, additional, Dru, Philippe, additional, Peron, Sophie, additional, Jager, Muriel, additional, Condamine, Thomas, additional, Pottin, Karen, additional, Romano, Séverine, additional, Steger, Julia, additional, Sinigaglia, Chiara, additional, Barreau, Carine, additional, Artigas, Gonzalo Quiroga, additional, Ruggiero, Antonella, additional, Fourrage, Cécile, additional, Kraus, Johanna E. M., additional, Poulain, Julie, additional, Aury, Jean-Marc, additional, Wincker, Patrick, additional, Quéinnec, Eric, additional, Technau, Ulrich, additional, Manuel, Michaël, additional, Momose, Tsuyoshi, additional, Houliston, Evelyn, additional, and Copley, Richard R., additional

Published
2018
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18. APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries

Author

Gribouval, Olivier, primary, Boyer, Olivia, additional, Knebelmann, Bertrand, additional, Karras, Alexandre, additional, Dantal, Jacques, additional, Fourrage, Cécile, additional, Alibeu, Olivier, additional, Hogan, Julien, additional, Dossier, Claire, additional, Tête, Marie Josèphe, additional, Antignac, Corinne, additional, and Servais, Aude, additional

Published
2018
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19. The ESCRT-II proteins are involved in shaping the sarcoplasmic reticulum in C. elegans

Author

Lefebvre, Christophe, Largeau, Céline, Michelet, Xavier, Fourrage, Cécile, Maniere, Xavier, Matic, Ivan, Legouis, Renaud, Culetto, Emmanuel, Autophagie et Développement ( OTOFAJ ), Département Biologie Cellulaire ( BioCell ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Brigham and Women's Hospital [Boston], Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Association pour la Recherche sur le Cancer [grant number SFI20111203826], ANR-12-BSV2-0018,EAT,Analyse mécanistique et implications fonctionnelles de l'autophagie au cours du développement embryonnaire ( 2012 ), LOISEAU, Maryse, BLANC - Analyse mécanistique et implications fonctionnelles de l'autophagie au cours du développement embryonnaire - - EAT2012 - ANR-12-BSV2-0018 - BLANC - VALID, Autophagie et Développement (OTOFAJ), Département Biologie Cellulaire (BioCell), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-12-BSV2-0018,EAT,Analyse mécanistique et implications fonctionnelles de l'autophagie au cours du développement embryonnaire(2012)

Subjects
Muscle Cells, Endosomal Sorting Complexes Required for Transport, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Sarcoplasmic reticulum, Ryanodine Receptor Calcium Release Channel, macromolecular substances, Organelle shape, musculoskeletal system, [SDV] Life Sciences [q-bio], Animals, Calcium, ESCRT-II, Caenorhabditis elegans Proteins, Caenorhabditis elegans, Muscle Contraction, Research Article
Abstract

International audience; The sarcoplasmic reticulum is a network of tubules and cisternae localized in close association with the contractile apparatus, and regulates Ca(2+)dynamics within striated muscle cell. The sarcoplasmic reticulum maintains its shape and organization despite repeated muscle cell contractions, through mechanisms which are still under investigation. The ESCRT complexes are essential to organize membrane subdomains and modify membrane topology in multiple cellular processes. Here, we report for the first time that ESCRT-II proteins play a role in the maintenance of sarcoplasmic reticulum integrity inC. elegans ESCRT-II proteins colocalize with the sarcoplasmic reticulum marker ryanodine receptor UNC-68. The localization at the sarcoplasmic reticulum of ESCRT-II and UNC-68 are mutually dependent. Furthermore, the characterization of ESCRT-II mutants revealed a fragmentation of the sarcoplasmic reticulum network, associated with an alteration of Ca(2+)dynamics. Our data provide evidence that ESCRT-II proteins are involved in sarcoplasmic reticulum shaping.

Published
2016

20. No correlation between mtDNA amount and methylation levels at the CpG island of POLG exon 2 in wild-type and mutant human differentiated cells

Author

Steffann, Julie, primary, Pouliet, Aurore, additional, Adjal, Houda, additional, Bole, Christine, additional, Fourrage, Cécile, additional, Martinovic, Jelena, additional, Rolland-Galmiche, Louise, additional, Rotig, Agnes, additional, Tores, Frédéric, additional, Munnich, Arnold, additional, and Bonnefont, Jean-Paul, additional

Published
2017
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21. Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation

Author

Kim, Rathana, Boissel, Nicolas, Touzart, Aurore, Leguay, Thibaut, Thonier, Florian, Thomas, Xavier, Raffoux, Emmanuel, Huguet, Françoise, Villarese, Patrick, Fourrage, Cécile, Passini, Loïc, Hunault, Mathilde, Lepretre, Stéphane, Chevallier, Patrice, Braun, Thorsten, Lhéritier, Véronique, Chantepie, Sylvain, Maury, Sébastien, Escoffre, Martine, Tavernier, Emmanuelle, Chalandon, Yves, Graux, Carlos, Macintyre, Elizabeth, Ifrah, Norbert, Asnafi, Vahid, Dombret, Hervé, and Lhermitte, Ludovic

Abstract

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2components but not with K/NRAS. IL7Rp mutated (IL7Rpmut) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7RpWT) T-ALL (p= 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p= 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rpmutpatients whereas it was of marked benefit to IL7RpWTcases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

Published
2020
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22. Identification et caractérisation d’ARNs localiséset de protéines maternelschez Clytia hemisphaerica

Author

Fourrage, Cécile, Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), UPMC - Sorbonne University, and Houliston, Evelyn

Subjects
cell division, facteurs maternels, [SDV.BA]Life Sciences [q-bio]/Animal biology, RNA localization, Clytia hemisphaerica, mitochondria, division cellulaire, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, bioluminescence, mitochondrie, maternal factors, développement embryonnaire, embryonic development, oeuf, GFPs, egg, localisation des ARNs, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract

In all metazoans, the first steps of embryonic development until the beginning of transcriptionfrom the zygotic genome, are governed by maternal factors. Accumulated and positioned inthe egg during its formation, these molecules constitute nutritive resources and informationnecessary to direct establishement of the embryonic body plan, for example by determiningaxes of embryonic polarity and specifying development of the germ line. This thesisillustrates by three examples the important roleof maternal factors for development in thecnidarian Clytia hemisphaerica. Oogenesis and embryogenesis are easily accessible in thisemerging model species, whose phylogenetic position at the base of the metazoan tree canhelp to understand ancestral mechanisms of animal biology. The first example concerns thephenomenon of mRNA localisation. Following the discovery of the determinant mRNAsCheFz1, CheFz3 and CheWnt3, I identified a new set of maternal RNAs, localised in differentpatterns within the Clytia egg. I initiated the study of the localization mechanisms of thesemRNAs through a primary analysis of the 3’UTRs sequences and observation of thebehaviour of microinjected fluorescent mRNAs. The particular case of BicD mRNA andprotein, associated with dynein-dependent mRNA transport, was examined in more detail.The second part of my thesis concerns the centriolar protein Poc1, encoded by one of thecharacterized maternal mRNAs. Analysis of Poc1 in Clytia revealed a conserved localizationof the protein at the centrosome and a requirement in cell division and gastrulation. The thirdpart of my thesis concerns two linked protein families: Green Fluorescent Proteins and thebioluminescent proteins Clytins. Surprisingly, one GFP gene and one Clytin gene were foundin Clytia to be maternally expressed, and their corresponding proteins to be co-targeted tomitochondria. In vivo energy transfer was demonstrated in eggs, showing functional couplingof these two maternal proteins. These observations suggest co evolution of the two genes andclosely coupled functions. Overall, my thesis has provided new knowledge about the maternalphase in the development of an emergent model species.; Chez les métazoaires, les premières phases du développement embryonnaire sont assurées pardes facteurs maternels de nature variée, en attendant le démarrage de l’expression du génomezygotique. Accumulées et positionnées dans l’oeuf au cours de sa formation, ces moléculesconstituent les ressources en nutriments nécessaires et les informations permettant degouverner la mise en place du plan d’organisation de l’embryon, par exemple par ladétermination des axes de polarité et de la lignée germinale. Cette thèse illustre le rôlefondamental de facteurs maternels dans le développement embryonnaire chez le cnidaireClytia hemisphaerica à travers trois volets. L’ovogenèse et l’embryogenèse sont facilementaccessibles dans cet animal qui, par sa position phylogénétique, peut aider à la compréhensiondes processus ancestraux, à la base de la construction des (eu)métazoaires. Le premier voletde cette thèse aborde le phénomène de localisation des ARNs. A la suite de la découverte desARNs déterminants CheFz1, CheFz3 et CheWnt3, de nouveaux ARNs maternels, localisésdans l’oeuf de Clytia selon différents patrons, ont été identifiés. L’étude des mécanismes delocalisation de ces ARNs a été débutée par une première analyse des séquences 3’UTRs etl’observation du comportement d’ARNs fluorescents injectés dans les ovocytes en cours dematuration. L’étude du cas particulier de l’ARN de CheBicD et de sa protéine, associée autransport dynéine-dépendant d’ARNs, a également été initiée. Le deuxième volet concerne laprotéine centriolaire Poc1, codée par un des ARNs maternels caractérisés. L’étude de Poc1chez Clytia hemisphaerica a montré que cette protéine avait une localisation centrosomale etqu’elle était nécessaire pour assurer les divisions cellulaires et la gastrulation. Le troisièmevolet concerne deux familles de protéines particulières : les protéines fluorescentes GFP et lesphotoprotéines Clytines. De façon surprenante, j’ai trouvé que chez Clytia, un gène GFP ainsiqu’un gène Clytine sont spécifiquement exprimés dans les ovocytes et leurs protéines coadresséesaux mitochondries. Un transfert d’énergie in vivo a été mis en évidence dans lesoeufs, indiquant un couplage fonctionnel des deux protéines maternelles. Ces observationssuggèrent une co-évolution de ces 2 gènes et des fonctions étroitement liées. Dans l’ensemble,ce travail de thèse a fourni de nouvelles connaissances concernant la phase maternelle dudéveloppement chez une espèce modèle émergente.

Published
2010

25. No correlation between mtDNA amount and methylation levels at the CpG island of POLGexon 2 in wild-type and mutant human differentiated cells

Author

Steffann, Julie, Pouliet, Aurore, Adjal, Houda, Bole, Christine, Fourrage, Cécile, Martinovic, Jelena, Rolland-Galmiche, Louise, Rotig, Agnes, Tores, Fréédéééric, Munnich, Arnold, and Bonnefont, Jean-Paul

Abstract

BackgroundWhile mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human.MethodsWe have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls.ResultsVery high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed.ConclusionsThis study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.

Published
2017
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27. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study.

Author

Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, and Dias, Jorge Amil

Published
2021
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28. Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study

Author

Olivier Alibeu, P. Tounian, Nadia Siala, Michela Tempia-Caliera, Jean-Pierre Hugot, Sabine Rakotobe, Christelle Lenoir, Anne Breton, Caterina Strisciuglio, Víctor Manuel Navas-López, Jan Melek, Alain Fischer, Frédéric Rieux-Laucat, Marie-Claude Stolzenberg, Eric Jeziorski, Yago González-Lama, Bénédicte Pigneur, Mongi Ben Hariz, Marina Aloi, Sylvain Latour, Fabienne Mazerolles, Christian Breuer, Julie Bruneau, Clara Crémilleux, Cecile Pelatan, Vaidotas Urbonas, Alexandre Fabre, Nadine Cerf-Bensussan, Frank M. Ruemmele, Luisa Mearin, Capucine Picard, Georgia Malamut, Neslihan Gurcan, Anders Paerregaard, Isabel Pinto Pais, Dan Turner, István Máttyus, Julie Rebeuh, Jiri Bronsky, Sylvain Hanein, Peter Lewindon, Rémi Duclaux-Loras, Graziella Guariso, Anne Bourrier, Odul Egritas Gurkan, Janos Major, Stéphanie Willot, Mara Cananzi, Marianna Parlato, Claudio Romano, Alain Lachaux, Matjaz Homan, Jorge Amil Dias, Eva Lévy, A Fischer, Stéphanie Coopman, Jan Krzysztof Nowak, Fernando Magro, Clémentine Dumant-Forest, Stephan Buderus, Bernadette Bègue, Fabienne Charbit-Henrion, Olivier Goulet, Evi Karanika, Alain Dabadie, Emmanuel Mas, Marta German Diaz, Cécile Fourrage, Rosa Lima, Charbit-Henrion, Fabienne, Parlato, Marianna, Hanein, Sylvain, Duclaux-Loras, Rémi, Nowak, Jan, Begue, Bernadette, Rakotobe, Sabine, Bruneau, Julie, Fourrage, Cécile, Alibeu, Olivier, Rieux-Laucat, Frédéric, Lévy, Eva, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Latour, Sylvain, Lenoir, Christelle, Fischer, Alain, Picard, Capucine, Aloi, Marina, Dias, Jorge Amil, Hariz, Mongi Ben, Bourrier, Anne, Breuer, Christian, Breton, Anne, Bronsky, Jiri, Buderus, Stephan, Cananzi, Mara, Coopman, Stéphanie, Crémilleux, Clara, Dabadie, Alain, Dumant-Forest, Clémentine, Gurkan, Odul Egrita, Fabre, Alexandre, Fischer, Aude, Diaz, Marta German, Gonzalez-Lama, Yago, Goulet, Olivier, Guariso, Graziella, Gurcan, Neslihan, Homan, Matjaz, Hugot, Jean-Pierre, Jeziorski, Eric, Karanika, Evi, Lachaux, Alain, Lewindon, Peter, Lima, Rosa, Magro, Fernando, Major, Jano, Malamut, Georgia, Mas, Emmanuel, Mattyus, Istvan, Mearin, Luisa M, Melek, Jan, Navas-Lopez, Victor Manuel, Paerregaard, Ander, Pelatan, Cecile, Pigneur, Bénédicte, Pais, Isabel Pinto, Rebeuh, Julie, Romano, Claudio, Siala, Nadia, Strisciuglio, Caterina, Tempia-Caliera, Michela, Tounian, Patrick, Turner, Dan, Urbonas, Vaidota, Willot, Stéphanie, Ruemmele, Frank M, and Cerf-Bensussan, Nadine

Subjects
VEO-IBD, business.industry, Yield (finance), monogenic IBD, next generation sequencing, very early onset IBD, Gastroenterology, Inflammatory Bowel Diseases, Genetics and molecular epidemiology, Original Articles, General Medicine, monogenic disorders, Bioinformatics, Very early onset, DNA sequencing, paediatrics, Editor's Choice, Multicenter study, TNGS, Medicine, genetics and molecular epidemiology, business
Abstract

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Published
2020

29. Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study.

Author

Philippot Q, Kannengiesser C, Debray MP, Gauvain C, Ba I, Vieri M, Gondouin A, Naccache JM, Reynaud-Gaubert M, Uzunhan Y, Bondue B, Israël-Biet D, Dieudé P, Fourrage C, Lainey E, Manali E, Papiris S, Wemeau L, Hirschi S, Mal H, Nunes H, Schlemmer F, Blanchard E, Beier F, Cottin V, Crestani B, and Borie R

Subjects
Exoribonucleases, Humans, Mutation genetics, Retrospective Studies, Idiopathic Pulmonary Fibrosis genetics, Lung Diseases, Interstitial genetics
Abstract

Background and Objective: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations., Methods: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network., Results: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation., Conclusion: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed., (© 2022 Asian Pacific Society of Respirology.)

Published
2022
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30. Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders.

Author

Montaut S, Tranchant C, Drouot N, Rudolf G, Guissart C, Tarabeux J, Stemmelen T, Velt A, Fourrage C, Nitschké P, Gerard B, Mandel JL, Koenig M, Chelly J, and Anheim M

Subjects
Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Cerebellar Ataxia genetics, Child, Child, Preschool, Chorea diagnosis, Chorea genetics, Dystonic Disorders genetics, Female, Genotype, High-Throughput Nucleotide Sequencing economics, Humans, Infant, Male, Middle Aged, Myoclonus diagnosis, Myoclonus genetics, Parkinsonian Disorders genetics, Phenotype, Prospective Studies, Sequence Analysis, DNA economics, Exome Sequencing economics, Young Adult, High-Throughput Nucleotide Sequencing methods, Movement Disorders diagnosis, Movement Disorders genetics, Sequence Analysis, DNA methods, Exome Sequencing methods
Abstract

Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis., Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders., Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016., Main Outcomes and Measures: Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders., Results: Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater., Conclusions and Relevance: High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

Published
2018
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31. Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study.

Author

Charbit-Henrion F, Parlato M, Hanein S, Duclaux-Loras R, Nowak J, Begue B, Rakotobe S, Bruneau J, Fourrage C, Alibeu O, Rieux-Laucat F, Lévy E, Stolzenberg MC, Mazerolles F, Latour S, Lenoir C, Fischer A, Picard C, Aloi M, Dias JA, Hariz MB, Bourrier A, Breuer C, Breton A, Bronsky J, Buderus S, Cananzi M, Coopman S, Crémilleux C, Dabadie A, Dumant-Forest C, Gurkan OE, Fabre A, Fischer A, Diaz MG, Gonzalez-Lama Y, Goulet O, Guariso G, Gurcan N, Homan M, Hugot JP, Jeziorski E, Karanika E, Lachaux A, Lewindon P, Lima R, Magro F, Major J, Malamut G, Mas E, Mattyus I, Mearin LM, Melek J, Navas-Lopez VM, Paerregaard A, Pelatan C, Pigneur B, Pais IP, Rebeuh J, Romano C, Siala N, Strisciuglio C, Tempia-Caliera M, Tounian P, Turner D, Urbonas V, Willot S, Ruemmele FM, and Cerf-Bensussan N

Subjects
Adolescent, Age of Onset, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Inflammatory Bowel Diseases therapy, Male, Predictive Value of Tests, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases etiology
Abstract

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment., Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally., Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES., Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD., (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Published
2018
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32. The ESCRT-II proteins are involved in shaping the sarcoplasmic reticulum in C. elegans.

Author

Lefebvre C, Largeau C, Michelet X, Fourrage C, Maniere X, Matic I, Legouis R, and Culetto E

Subjects
Animals, Caenorhabditis elegans Proteins metabolism, Calcium metabolism, Ryanodine Receptor Calcium Release Channel metabolism, Caenorhabditis elegans metabolism, Endosomal Sorting Complexes Required for Transport metabolism, Muscle Cells metabolism, Muscle Contraction physiology, Sarcoplasmic Reticulum metabolism
Abstract

The sarcoplasmic reticulum is a network of tubules and cisternae localized in close association with the contractile apparatus, and regulates Ca(2+)dynamics within striated muscle cell. The sarcoplasmic reticulum maintains its shape and organization despite repeated muscle cell contractions, through mechanisms which are still under investigation. The ESCRT complexes are essential to organize membrane subdomains and modify membrane topology in multiple cellular processes. Here, we report for the first time that ESCRT-II proteins play a role in the maintenance of sarcoplasmic reticulum integrity inC. elegans ESCRT-II proteins colocalize with the sarcoplasmic reticulum marker ryanodine receptor UNC-68. The localization at the sarcoplasmic reticulum of ESCRT-II and UNC-68 are mutually dependent. Furthermore, the characterization of ESCRT-II mutants revealed a fragmentation of the sarcoplasmic reticulum network, associated with an alteration of Ca(2+)dynamics. Our data provide evidence that ESCRT-II proteins are involved in sarcoplasmic reticulum shaping., (© 2016. Published by The Company of Biologists Ltd.)

Published
2016
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