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1. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author

Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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 ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, 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 ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract

PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

Published
2020

2. Risk factors of clinical dysimmune manifestations in a cohort of 86 children with 22q11.2 deletion syndrome: A retrospective study in France

Author

Pierre Portales, Pierre Sarda, Marie-José Perez, Gregory Marin, Claire Lozano, Eric Jeziorski, Nicolas Nagot, Pascal Amedro, Perrine Mahe, Thierry Vincent, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), 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), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), MORNET, Dominique, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
0301 basic medicine, Male, lymphocytes, Allergy, 030105 genetics & heredity, medicine.disease_cause, Severity of Illness Index, Autoimmunity, T-Lymphocyte Subsets, Prevalence, infections, Child, Genetics (clinical), autoimmunity, 3. Good health, Immunoglobulin Isotypes, Phenotype, Child, Preschool, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, France, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune Diseases, 03 medical and health sciences, 22q11 Deletion Syndrome, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Internal medicine, Genetics, medicine, DiGeorge Syndrome, Hypersensitivity, Humans, Risk factor, Autoimmune disease, 22q11 deletion syndrome, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, dysimmunity, Infant, Retrospective cohort study, medicine.disease, Confidence interval, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

International audience; In this study, we describe the biological immune profiles and clinical dysimmune manifestations (infections, autoimmune diseases, and allergies) of patients with 22q11.2 deletion syndrome with the aim of determining risk factors for clinical events. This retrospective study concerned all the patients with 22q11 deletion syndrome attending the Montpellier University Hospital from January 1, 1992, to December 31, 2014 who had at least one immune investigation before the age of 18. We analyzed the clinical features, biological tests and the course of infections, autoimmunity, and allergy of 86 children. Among these 86 children, 48 (59%) had a low T lymphocyte level. Twenty-nine patients (34%) had a severe infection. The only risk factor for severe infection was the low level of CD4+ T-cells (OR: 3.3; 95% confidence interval (CI) [1.020-11.108]). Eleven patients (13%) developed an autoimmune disease; the only risk factor was an antecedent of severe infection (OR: 4.1; 95% CI [1.099-15.573]). Twenty-three patients (27%) had allergic episodes. A low level of CD8+ T-cells (OR: 3.2; 95% CI [1.07-9.409]) was significantly associated with allergy manifestations. Patients with 22q11 deletion syndrome have a high rate of dysimmune manifestations. We found statistic correlations among CD4+ T-cell count, infectious manifestations, and autoimmunity.

Published
2019

3. Comparison between potassium chloride and lidocaine as lethal agents for feticide in termination of pregnancy

Author

Pierre Boulot, E. Mousty, A. Ménard, Florent Fuchs, Y. Musizzano, Marie-José Perez, C. Dumont, R. Rayssiguier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [Montpellier], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Saint Jean de Perpignan, Centre de recherche en épidémiologie et santé des populations (CESP), and 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)

Subjects
medicine.medical_specialty, Lidocaine, Potassium, MEDLINE, chemistry.chemical_element, Abortion, 03 medical and health sciences, 0302 clinical medicine, Feticide, medicine, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Abortifacient agent, ComputingMilieux_MISCELLANEOUS, Pregnancy, 030219 obstetrics & reproductive medicine, Radiological and Ultrasound Technology, Obstetrics, business.industry, Obstetrics and Gynecology, General Medicine, medicine.disease, 3. Good health, Reproductive Medicine, chemistry, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience

Published
2019

4. Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Author

Philippe Khau Van Kien, Flora Silbermann, Cécile Jeanpierre, Bharti Morar, Alexandre Benmerah, Camille Humbert, Rémi Salomon, Marie-José Perez, Luba Kalaydjieva, Mohammed Zarhrate, Cécile Masson, Patricia Blanchet, Corinne Antignac, Joelle Roume, Brigitte Leroy, Laurence Heidet, Sophie Saunier, Yuliya Petrov, Frédéric Tores, Olivier Gribouval, Mélanie Parisot, Benmerah, Alexandre, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The University of Western Australia (UWA), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], and Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA)

Subjects
Male, Pathology, 030232 urology & nephrology, Kidney development, [SDV.GEN] Life Sciences [q-bio]/Genetics, Kidney, medicine.disease_cause, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, Genetics(clinical), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Homozygote, Hypoplasia, Pedigree, 3. Good health, Bilateral Renal Agenesis, medicine.anatomical_structure, Female, Kidney Diseases, Erratum, Integrin alpha Chains, medicine.medical_specialty, Genes, Recessive, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Congenital Abnormalities, 03 medical and health sciences, Fetus, Report, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Renal agenesis, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Dysplasia, Urogenital Abnormalities, business, 030217 neurology & neurosurgery
Abstract

International audience; Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.

Published
2014
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5. OP02.06: Noonan syndrome fetal phenotype with PTPN11, RIT1, RAF1 and NRAS pathogenic variant: ultrasound data, fetopathology study and literature review

Author

Marie-José Perez, F. Grosjean, T. Attie, Jean-Michel Faure, David Geneviève, C. Dauge, E. Mousty, Florent Fuchs, F. Pelluard, and A. Lamouroux

Subjects
Neuroblastoma RAS viral oncogene homolog, Pathology, medicine.medical_specialty, Fetus, Radiological and Ultrasound Technology, business.industry, Ultrasound, Obstetrics and Gynecology, General Medicine, medicine.disease, Phenotype, PTPN11, Reproductive Medicine, medicine, Noonan syndrome, Radiology, Nuclear Medicine and imaging, business
Published
2019

6. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases

Author

Frédérique Jossic, Férecheté Razavi, Dominique Gaillard, Louise Devisme, Anne-Lise Delezoide, Carla Fernandez, Madeleine Joubert, Jelena Martinovic, Blandine Fabre, Nathalie Drouot, Homa Adle-Biassette, Marie Gonzales, Mario Tosi, Martine Bucourt, Dominique Carles, Nicole Laurent, Bettina Bessières, Martine Sinico, Annie Laquerrière, Daniel Satge, Thierry Frebourg, Sophie Blesson, Jacques Benichou, Philippe Loget, Marie-José Perez, Catherine Fallet-Bianco, Anne-Marie Beaufrère, Anne Bazin, Pierre Gressens, Pascale Saugier-Veber, Laurence Loeuillet, Frédérique Dijoud, Brigitte Leroy, and Pascale Marcorelles

Subjects
Pathology, medicine.medical_specialty, Neural Cell Adhesion Molecule L1, Biology, Corpus callosum, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Pregnancy, medicine, Humans, Abnormalities, Multiple, L1 syndrome, 030304 developmental biology, Phenocopy, 0303 health sciences, Corpus Callosum Agenesis, Cerebral Aqueduct, Infant, Newborn, Genetic Diseases, X-Linked, medicine.disease, Hypoplasia, Pedigree, 3. Good health, Hydrocephalus, Phenotype, Agenesis, Mutation, Female, Neurology (clinical), Nervous System Diseases, Differential diagnosis, 030217 neurology & neurosurgery
Abstract

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.

Published
2013

7. La conscience pas si bête

Author

Marie José Perez and Marie José Perez

Abstract

Nous vivons aujourd'hui dans des sociétés où le rationalisme est roi. Par la négation de certains phénomènes inexpliqués, nous tuons le divin de ce monde et nous annihilons, de ce fait, une partie de ce qui fait notre humanité : un cœur spirituel, que chacun de nous possède, connecté directement à la source infinie de vie. La communication animale est un des nombreux moyens de réveiller la véritable conscience qui sommeille en nous.

Published
2015

8. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Author

Marie, Vincent, David, Geneviève, Agnès, Ostertag, Sandrine, Marlin, Didier, Lacombe, Dominique, Martin-Coignard, Christine, Coubes, Albert, David, Stanislas, Lyonnet, Catheline, Vilain, Anne, Dieux-Coeslier, Sylvie, Manouvrier, Bertrand, Isidor, Marie-Line, Jacquemont, Sophie, Julia, Valérie, Layet, Sophie, Naudion, Sylvie, Odent, Laurent, Pasquier, Sybille, Pelras, Nicole, Philip, Geneviève, Pierquin, Fabienne, Prieur, Nisrine, Aboussair, Tania, Attie-Bitach, Geneviève, Baujat, Patricia, Blanchet, Catherine, Blanchet, Hélène, Dollfus, Bérénice, Doray, Elise, Schaefer, Patrick, Edery, Fabienne, Giuliano, Alice, Goldenberg, Cyril, Goizet, Agnès, Guichet, Christian, Herlin, Laetitia, Lambert, Bruno, Leheup, Jelena, Martinovic, Sandra, Mercier, Cyril, Mignot, Marie-Laure, Moutard, Marie-José, Perez, Lucile, Pinson, Jacques, Puechberty, Marjolaine, Willems, Hanitra, Randrianaivo, Kateline, Szakszon, Kateline, Szaskon, Annick, Toutain, Alain, Verloes, Jacqueline, Vigneron, Elodie, Sanchez, Pierre, Sarda, Jean-Louis, Laplanche, Corinne, Collet, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Génétique Humaine, Université de Liège-CHU Liège, 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 de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), 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 ), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre [Strasbourg], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 ), 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 ), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale, Head of the Department of Medical Genetics, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut de Génétique et Développement de Rennes ( IGDR ), 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 ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Bretonneau-CHRU Tours, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Lavoisier de Versailles ( ILV ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), 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 ), 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 Necker - Enfants Malades [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], 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), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Adult, Male, 0301 basic medicine, Franceschetti syndrome, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Treacher Collins syndrome, Young Adult, 03 medical and health sciences, medicine, Humans, Base sequence, POLR1D, Amino Acid Sequence, Child, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Sequence Deletion, phenotype–genotype correlations, Base Sequence, [ SDV ] Life Sciences [q-bio], Nuclear Proteins, Large series, DNA-Directed RNA Polymerases, Mandibulofacial dysostosis, Middle Aged, Peptide Elongation Factors, Phosphoproteins, medicine.disease, Dermatology, 3. Good health, Surgery, TCOF1, 030104 developmental biology, Mutation, Microcephaly, Female, Mandibulofacial Dysostosis
Abstract

International audience; Purpose - Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. Methods - We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. Results - We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Conclusion - Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

Published
2016

9. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies

Author

Annie Laquerrière, Dominique Bonneau, Fabien Guimiot, Françoise Menez, Bettina Bessières, Nicole Bigi, Agnès Liprandi, C. Bouchet, Dominique Figarella-Branger, Tania Attié-Bitach, Elisabeth Alanio, Dominique Gaillard, Stéphane Triau, Catherine Fallet-Bianco, Anne-Lise Delezoide, Madeleine Joubert, Martine Bucourt, Marie-José Perez, Pascale Marcorelles, Sophie Delahaye, Patricia Blanchet, Fanny Pelluard, Bernard Gasser, Maryse Bonnières, Louise Devisme, Sophie Patrier, Nicole Laurent, Marie Gonzales, Dominique Carles, Anne Bazin, Philippe Loget, B. Clarisse, Jelena Martinovic, Férechté Encha-Razavi, Sandrine Vuillaumier-Barrot, Caroline Rouleau, and Nathalie Seta

Subjects
Male, Pathology, medicine.medical_specialty, Cobblestone Lissencephaly, Lissencephaly, Biology, N-Acetylglucosaminyltransferases, Mannosyltransferases, Fetus, Bone plate, medicine, OMIM : Online Mendelian Inheritance in Man, Humans, Pentosyltransferases, Muscular dystrophy, Dystroglycans, Walker–Warburg syndrome, Infant, Newborn, Brain, Membrane Proteins, Proteins, Cortical dysplasia, medicine.disease, Dysplasia, Female, Neurology (clinical)
Abstract

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or ‘cobblestone’ brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker–Warburg syndrome, muscle–eye–brain and Fukuyama muscular dystrophy. Mutations in POMT1 , POMT2 , POMGNT1 , LARGE , FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria . After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 ( 8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32–50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1 , POMT2 , POMGNT1 , LARGE and FKRP . Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s). * Abbreviations : MDDGA : muscular congenital α-dystroglycanopathy with brain and eye anomalies OMIM : Online Mendelian Inheritance in Man

Published
2012

10. Epiphyseal punctate calcifications (stippling) in complete trisomy 9

Author

Jean-Michel Faure, David Geneviève, Haissam Rahil, Pierre Boulot, Anouck Schneider, Nami Wadih, Marie-José Perez, Nicole Bigi, Patricia Blanchet, Alain Couture, Pierre Sarda, Anne-Marie Chaze, Geneviève Lefort, and Caroline Rouleau

Subjects
Adult, Pathology, medicine.medical_specialty, Aneuploidy, Trisomy, Biology, Trisomy 9, Ultrasonography, Prenatal, Pregnancy, medicine, Humans, Genetics (clinical), Stippling (dentistry), Bone Diseases, Developmental, Calcinosis, Obstetrics and Gynecology, Epiphyseal punctate calcifications, Anatomy, medicine.disease, Epiphyseal calcification, Female, Chromosomes, Human, Pair 9, Epiphyses, Abortion, Eugenic, Epiphyseal stippling, Calcification
Published
2009

11. Decreased Full Breastfeeding, Altered Practices, Perceptions, and Infant Weight Change of Prepregnant Obese Women: A Need for Extra Support

Author

Régis Hankard, Clarisse Multon, Marie-José Perez, P. Christin, Emmanuelle Barroso, Valérie Goua, Elise Mok, and Lorraine Piguel

Subjects
medicine.medical_specialty, Birth weight, Breastfeeding, Weight Gain, Pregnancy, Surveys and Questionnaires, Birth Weight, Humans, Medicine, Obesity, business.industry, Obstetrics, Weight change, Infant, medicine.disease, Breast Feeding, Attitude, Pediatrics, Perinatology and Child Health, Female, Breastfeeding difficulties, medicine.symptom, business, Breast feeding, Weight gain
Abstract

OBJECTIVE. The purpose of this work was to compare breastfeeding practices, perceptions, and infant weight change of prepregnant obese versus normal-weight mothers in the first 3 months postpartum. PATIENTS AND METHODS. For the prospective case-control study, obese mothers (prepregnant BMI ≥ 30 kg/m2) were matched with normal-weight mothers (18.5 ≤ prepregnant BMI < 25 kg/m2) according to initial infant feeding, parity, maternal age, ethnicity, and education. Participants completed an oral questionnaire in the hospital and a telephone interview at 1 and 3 months postpartum. RESULTS. Of 1432 mothers who had given birth at a university hospital in France, 10% were obese. Breastfeeding initiation was lower for obese (48%) versus normal-weight (64%) mothers. A total of 111 of 141 obese mothers were paired with 111 normal-weight mothers. Infant birth weight was similar for newborns of obese and normal-weight mothers. Among mothers who initiated breastfeeding, infant weight gain from 0 to 1 month was lower in breastfed infants of obese mothers compared to normal-weight mothers. Obese mothers were less likely to maintain full breastfeeding at 1 month and 3 months. The percentage of mothers breastfeeding to any extent did not differ between obese and reference women. Obese mothers more often felt uncomfortable breastfeeding in public at 3 months. Fewer obese mothers perceived that their milk supply was sufficient at 1 month and 3 months. Despite greater breastfeeding difficulties, obese mothers were less likely to seek support for breastfeeding in the first 3 months postpartum. CONCLUSIONS. Pediatricians and health professionals should recognize that obese mothers have different breastfeeding practices and perceptions. Extra support and intervention are needed among obese mothers during prenatal and early postnatal periods so that their children can benefit from breastfeeding.

Published
2008

12. Epithelial Phenotypes in the Developing Human Prostate

Author

Gaëlle Fromont, Marie-José Perez, Mokrane Yacoub, Guy Letellier, Pierre Levillain, and Olivier Cussenot

Subjects
Male, Pathology, medicine.medical_specialty, Histology, Population, Biology, Epithelium, Basal (phylogenetics), Fetus, Epidermal growth factor, Prostate, Proliferating Cell Nuclear Antigen, medicine, Humans, education, Aged, education.field_of_study, Tissue microarray, Middle Aged, Androgen receptor, medicine.anatomical_structure, Tissue Array Analysis, Keratins, Immunohistochemistry, Anatomy, Biomarkers, Immunostaining
Abstract

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.

Published
2007

13. A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR ) expression in vivo

Author

C. Raynal, Isabelle Rivals, Milena Magalhães, Nicole Bigi, Jessica Varilh, Anne Bergougnoux, Alessandro Liquori, Raphaël Chiron, Marie-José Perez, Mireille Claustres, Ahmed Saad Squalli-Houssaini, Marie des Georges, Albertina De Sario, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Référence Anomalies du Développement et Syndromes Malformatifs, and Centre Hospitalier Régional et Universitaire

Subjects
Male, Cancer Research, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Response Elements, Histones, cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Fetus, Pregnancy, Gene silencing, Humans, Enhancer, Molecular Biology, Lung, 030304 developmental biology, 0303 health sciences, Blood Cells, DNA methylation, promoter, biology, histone modifications, bivalent chromatin, Acetylation, fetal tissues, Molecular biology, Cystic fibrosis transmembrane conductance regulator, Histone, 030220 oncology & carcinogenesis, biology.protein, H3K4me3, Female, enhancers, Digestive System, Protein Processing, Post-Translational, Bivalent chromatin, Research Paper
Abstract

International audience; The genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells. In this work, we analyzed fetal (at different stages of pregnancy) and adult tissues and showed that, in digestive and lung tissues, which expressed CFTR, H3K4me3 was maintained in the promoter. Histone acetylation was high in the promoter and in two intronic enhancers, especially in fetal tissues. In contrast, in blood cells, which did not express CFTR, the bivalent chromatin was resolved (the promoter was labeled by the silencing mark H3K27me3). Cis-regulatory sequences were associated with lowly acetylated histones. We also provide evidence that the tissue-specific expression of CFTR is not regulated by dynamic changes of DNA methylation in the promoter. Overall, this work shows that a balance between activating and repressive histone modifications in the promoter and intronic enhancers results in the fine regulation of CFTR expression during development, thereby ensuring tissue specificity.

Published
2014

14. Existe-t-il une dysimmunité chez les enfants porteurs de la délétion 22q11.2 ? Étude rétrospective de la cohorte pédiatrique du centre de référence des anomalies du développement et syndromes malformatifs du CHU de Montpellier

Author

Eric Jeziorski, Nicolas Nagot, Pierre Portales, Marie-José Perez, Pierre Sarda, and Perrine Mahé

Subjects
Oncology, Pediatrics, Perinatology and Child Health, Hematology
Abstract

Le syndrome de deletion 22q11.2, syndrome deletionnel le plus frequent, est une entite clinique heterogene associant de facon variable une dysmorphie faciale, une cardiopathie, une hypoparathyroidie et un deficit immunitaire secondaire a une hypoplasie thymique. L’objectif de cette etude est d’etudier les profils immunitaires, cliniques et biologiques de ces patients, de decrire les complications dysimmmunitaires (infections, auto-immunite et allergies) auxquelles ils sont confrontes et d’en rechercher les facteurs de risque. Il s’agit d’une etude de cohorte retrospective, incluant tous les patients suivis au CHRU de Montpellier pour une deletion 22q11.2, ayant eu un bilan immunitaire avant l’âge de 18 ans. Nous avons recueilli les donnees cliniques et immunobiologiques (phenotypages lymphocytaires et dosages ponderaux des immunoglobulines) des patients, ainsi que les episodes infectieux, auto-immuns et allergiques. Au total, 86 patients ont ete inclus dans notre etude. Quarante-huit (59 %) avaient une lymphopenie T (avec 52 % de CD4 et 48 % de CD8 abaisses). Aucun des patients ne possedait d’IgG abaisse. Neuf pour cent d’entre eux avaient des IgA et 29 % des IgM sous la norme. Vingt-neuf patients (34 %) avaient fait une infection severe et 62 (72 %), des infections recurrentes. Le seul facteur de risque d’infection severe etait une lymphopenie CD4 (OR : 3,3 ; p = 0,04). Onze patients, soient 13 % avaient developpe une maladie auto-immune avec comme facteur de risque un antecedent d’infection severe (OR : 4,1 ; p = 0,04). Vingt-trois patients (27 %) ont presente des episodes allergiques avec comme facteur de risque une lymphopenie CD8 (OR : 3,2 ; p = 0,04). Des manifestations dysimmunitaires sont retrouvees de maniere frequente chez les patients porteurs de deletion 22q11 : infections, allergies et maladies auto-immunes. Notre etude semble montrer un lien entre dysimmunite, infections et lymphopenie CD4. Afin de confirmer et completer nos resultats, nous proposons la realisation d’une etude prospective afin de preciser cette atteinte immunologique et de mettre en evidence des marqueurs pronostiques fiables en vue d’ameliorer la prise en charge des patients.

Published
2016

15. Exon skipping as a therapeutic strategy applied to an RYR1 mutation with pseudo-exon inclusion causing a severe core myopathy

Author

John Rendu, Julie Brocard, Eric Denarier, Nicole Monnier, France Piétri-Rouxel, Cyriaque Beley, Nathalie Roux-Buisson, Brigitte Gilbert-Dussardier, Marie José Perez, Norma Romero, Luis Garcia, Joël Lunardi, Julien Fauré, Anne Fourest-Lieuvin, Isabelle Marty, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie Génétique et Moléculaire, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie Génétique et Moléculaire, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Thérapie des maladies du muscle strié, 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), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), INSERM U836, équipe 1, Physiopathologie du cytosquelette, ANTE-INSERM U836, équipe 13, Régulation dynamique et structurale du cytosquelette, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM, AFM, Fondation Daniel Ducoin, DRC Chu de Grenoble, Vivier de la Recherche de la Faculté de Médecine de Grenoble, Institut National de la Santé et de la Recherche Médicale (INSERM)-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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Grenoble Institut des Neurosciences (GIN), and Roux-Buisson, Nathalie

Subjects
Blotting, Western, Genetic Vectors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, medicine, Humans, Myopathy, Central Core, Myopathy, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Research Articles, 030304 developmental biology, DNA Primers, Calcium metabolism, RYR1, 0303 health sciences, Mutation, Ryanodine receptor, Reverse Transcriptase Polymerase Chain Reaction, Lentivirus, Ryanodine Receptor Calcium Release Channel, Exons, Genetic Therapy, medicine.disease, musculoskeletal system, Molecular biology, Exon skipping, Cell biology, HEK293 Cells, Gene Expression Regulation, Microscopy, Fluorescence, Molecular Medicine, Calcium, medicine.symptom, tissues, 030217 neurology & neurosurgery, Central core disease
Abstract

International audience; Central core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level.

Published
2013

16. Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations

Author

Julia Tantau, Martine Bucourt, Alain Kitzis, Laurence Loeuillet, Marie-José Perez, Anne-Lise Delezoide, Frédérique Jossic, Marine Legendre, Anne Bazin, Frédéric Bilan, Pauline Parisot, Amale Ichkou, Nicole Laurent, Fabien Guimiot, Michel Vekemans, Caroline Alby, Bettina Bessières, Catherine Fallet-Bianco, Brigitte Gilbert-Dussardier, Yves Ville, Tania Attié-Bitach, Marie Gonzales, Stanislas Lyonnet, Philippe Loget, Nicole Bigi, Roselyne Gesny, Maryse Bonnière, Brigitte Leroy, Houria Salhi, Chloé Quélin, Ferechté Razavi, Jelena Martinovic, Caroline Rouleau, and Géraldine Goudefroye

Subjects
Adult, Male, medicine.medical_specialty, Reproductive medicine, CHARGE syndrome, Fetus, Pregnancy, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Genetics (clinical), Retrospective Studies, Clinical pathology, business.industry, Obstetrics, DNA Helicases, Retrospective cohort study, medicine.disease, DNA-Binding Proteins, Pregnancy Complications, Phenotype, Chd7 gene, Agenesis, Mutation, Female, CHARGE Syndrome, business, Background charge
Abstract

Background CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. Method Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. Results Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype–genotype correlation. Conclusions Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.

Published
2012

17. NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases

Author

Marie-José Perez, Gioacchino Scarano, Dominique Martin-Coignard, Jacqueline Aziza, Joelle Roume, Marie Gonzales, Felicity Collins, Joyce El Hokayem, Valérie Cormier-Daire, Adeline Couvé, Philippe Loget, Geneviève Baujat, Anne-Lise Delezoide, Diana Johnson, Denise P. Cavalcanti, Céline Huber, Arnold Munnich, Annie Levy-Mozziconacci, Raymonde Bouvier, Martine Le Merrer, Geert Mortier, Marie-Pierre Cordier, and Jelena Martinovic

Subjects
Cytoplasmic Dyneins, Male, Genotype, Short rib polydactyly, Cell Cycle Proteins, Biology, Protein Serine-Threonine Kinases, Short Rib-Polydactyly Syndrome, medicine.disease_cause, Compound heterozygosity, environment and public health, Consanguinity, Genetic Heterogeneity, Fetus, Holoprosencephaly, Pregnancy, Genetics, medicine, Humans, Gene, Genetics (clinical), Genetic Association Studies, Mutation, Polydactyly, Genetic heterogeneity, Dysostosis, medicine.disease, NIMA-Related Kinase 1, Female, Human medicine
Abstract

Background The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance. Methods The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA. Results The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group. Conclusion This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.

Published
2012

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