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1. Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants – identification of 11 novel mutations in CYBB

Author

Leena Kainulainen, M. Hancart, John Rendu, Sylvain Beaumel, Julie Brault, D Plantaz, Bénédicte Vigne, G. Catho, C. Jarrassé, Vincent Barlogis, S. Drillon Haus, Yves Bertrand, Julien Fauré, Eric Jeziorski, M Houachée-Chardin, Virginie Gandemer, M. Revest, Michelle Mollin, Cécile Bost-Bru, Franck Fieschi, Laurence Eitenschenck, J. Kelecic, Marie José Stasia, Gérard Michel, Fanny Fouyssac, R. Traberg, D. Monnier, C. Dumeril, Nathalie Roux-Buisson, J-P Brion, CGD Diagnosis and Research Centre (CDiReC), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Inserm, U1216, Grenoble, France., Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-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)-Université Grenoble Alpes (UGA), European Project, Centre Hospitalier Universitaire [Grenoble] (CHU), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Neutrophils, Immunology, Mutation, Missense, Context (language use), Granulomatous Disease, Chronic, medicine.disease_cause, Cell Line, Young Adult, 03 medical and health sciences, Exon, 0302 clinical medicine, Chronic granulomatous disease, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Immunology and Allergy, Missense mutation, CYBB, Oxidase test, Mutation, Membrane Glycoproteins, NADPH oxidase, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Exons, Original Articles, NOX, medicine.disease, Molecular biology, 3. Good health, 030104 developmental biology, clinical severity, NADPH Oxidase 2, biology.protein, Female, X-linked CGD variants, 030215 immunology
Abstract

Summary Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910, X91− or X91+), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910-CGD and two X91−-CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD, whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

Published
2020
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2. Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome

Author

Pauline Le Tanno, Mathilde Folacci, Jean Revilloud, Laurence Faivre, Gabriel Laurent, Lucile Pinson, Pascal Amedro, Gilles Millat, Alexandre Janin, Michel Vivaudou, Nathalie Roux-Buisson, Julien Fauré, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
[SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, QH426-470, Bioinformatics, Catecholaminergic polymorphic ventricular tachycardia, Sudden death, Ryanodine receptor 2, 03 medical and health sciences, 0302 clinical medicine, Andersen–Tawil syndrome, Genetics, Medicine, Genetics (clinical), Loss function, 030304 developmental biology, Kir2.1 channel, 0303 health sciences, Pierre Robin sequence, catecholaminergic polymorphic ventricular tachycardia, Andersen-Tawil syndrome, business.industry, KCNJ2 variants, Periodic paralysis, Brief Research Report, medicine.disease, Phenotype, 3. Good health, cardiovascular system, Molecular Medicine, business, Rare disease, functionnal characterization
Abstract

Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.

Published
2021
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3. Challenging indication of cardioverter defibrillator implantation after sudden cardiac arrest in the very young: a case series of catecholaminergic polymorphic ventricular tachycardia secondary to de novo calmodulin p.Asn98Ser

Author

Alice Maltret, Damien Bonnet, Véronique Fressart, John Rendu, Fatima Azzahrae Benaich, Nathalie Roux-Buisson, Isabelle Denjoy, Hôpital Marie-Lannelongue, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], AP-HP - Hôpital Bichat - Claude Bernard [Paris], HAL-SU, Gestionnaire, Hôpital Marie Lannelongue, Centre Chirurgical Marie Lannelongue (CCML), Université Paris-Saclay, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Garnier, Sophie

Subjects
Cardiovascular event, medicine.medical_specialty, precipitating factors, almodulin, cardiac event, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Disease, 030204 cardiovascular system & hematology, Catecholaminergic polymorphic ventricular tachycardia, Implantable cardioverter-defibrillator, Sudden cardiac death, implantable defibrillator insertion, Cardioverter-Defibrillator, 03 medical and health sciences, 0302 clinical medicine, Calmodulin, Internal medicine, Case report, medicine, follow-up, Case Series, AcademicSubjects/MED00200, 030212 general & internal medicine, Shared decision-making, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Sudden cardiac arrest, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], parent, Cardiology, medicine.symptom, mutation, Cardiology and Cardiovascular Medicine, Complication, business, implantable defibrillators, professional supervision, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Calmodulinopathy is an emerging group of primary electrical disease with various, severe, and early onset phenotype. Sudden cardiac arrest (SCA)/death can be the first symptom and current medical management seems insufficient to prevent recurrences. Implantable cardioverter-defibrillator (ICD) in the young is challenging and can be harmful. Case summary We report the management of two very young boys (aged 3.5 and 5.5 years old) who survived an SCA due to calmodulin mutation responsible of a catecholaminergic polymorphic ventricular tachycardia phenotype. In both case, SCA had an adrenergic trigger. Despite SCA, ICD implantation was denied by the parents. After thorough discussion with the family, the patients were managed with solely betablocker treatment and loop recorder implantation. At last follow-up of 30 and 23 months, respectively, there were no recurrence of any cardiac event. Discussion The benefits of ICD implantation at a very young age must be weighed against the risk complication. In the youngest, whom recreative activities are under constant supervision, the decision, jointly made with the parents, could be to postpone ICD.

Published
2021
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4. Evaluation of patients’ needs to design and assess a patient education program in cancer pain

Author

Marie-Christine Grach, Cyril Guillaumé, Bénédicte Clarisse, A. Le Chevalier, Rachel Bignon, Alexandra Leconte, V Sep Hieng, J Le Garrec, Nathalie Roux, C Bechet, Sonia Cauchin, Natacha Heutte, Marie-Claude Ropartz, C. Delorme, Cécile Bisson, Idlir Licaj, Maud Gicquère, and Virginie Prevost

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Persistent pain, Population, Pain relief, Pain management, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Anesthesiology and Pain Medicine, 030202 anesthesiology, Pain assessment, Therapeutic patient education, Physical therapy, Medicine, business, Cancer pain, education, 030217 neurology & neurosurgery, Patient education
Abstract

Purpose: Patient education constitutes a relevant strategy to improve pain management. In the field of therapeutic patient education (TPE), we aimed 1) to assess pain impact in cancer patients, 2) to identify patients' educative needs in pain management, and 3) to refine research criteria for its future evaluation. Patients and methods: Pain intensity, relief and interference were assessed in 75 cancer patients with unbalanced background pain. Self-assessment questionnaire evaluated i) patients' pain management and ii) their knowledge and needs in TPE. Results: Most patients experienced pain for more than 6 months and 41.6% reported adequate pain relief. Understanding pain and pain management were major patients' preferences (>58%). Most patients declared they knew their pain treatments, but fewer than half of them were able to name them. However, education concerning pain treatment was considered as essential in

Published
2019
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5. Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq

Author

Faris Ghalib Bakri, Michelle Mollin, Sylvain Beaumel, Bénédicte Vigne, Nathalie Roux-Buisson, Adel Mohammed Al-Wahadneh, Raed Mohammed Alzyoud, Wail Ahmad Hayajneh, Ammar Khaled Daoud, Mohammed Elian Abu Shukair, Mansour Fuad Karadshe, Mahmoud Mohammad Sarhan, Jamal Ahmad Wadi Al-Ramahi, Julien Fauré, John Rendu, Marie Jose Stasia, Division of Infectious Diseases, Department of Medicine, Jordan University Hospital, CGD Diagnosis and Research Centre (CDiReC), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Division of Immunology, Department of Pediatric, Queen Rani Children's Hospital, Division of Immunology, Department of Pediatrics, Division of Infectious Diseases, Department of Pediatrics, Jordan University of Science & Technology, Division of Immunology, Jo PAIR clinic, Josante Medical Center, Sarhan Oncology and Stem Cell Clinics, Adjunct Faculty, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-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)-Université Grenoble Alpes (UGA), and Centre Hospitalier Universitaire [Grenoble] (CHU)

Subjects
Male, chronic granulomatous disease, Granulomatous Disease, Chronic, medicine.disease_cause, Consanguinity, 0302 clinical medicine, Chronic granulomatous disease, Genes, X-Linked, Superoxides, immune system diseases, hemic and lymphatic diseases, Immunology and Allergy, Medicine, Child, Original Research, Genetics, 0303 health sciences, Mutation, education.field_of_study, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], autosomal recessive, 3. Good health, Child, Preschool, Iraq, Female, Immunodeficiency disorder, Adult, lcsh:Immunologic diseases. Allergy, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Immunology, Population, Genes, Recessive, Young Adult, 03 medical and health sciences, Humans, CYBB, Sibling, education, Gene, 030304 developmental biology, Jordan, NADPH oxidase, business.industry, Infant, NADPH Oxidases, medicine.disease, innate immunodeficiency, Genetic marker, founder mutation, business, lcsh:RC581-607, 030215 immunology
Abstract

Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (CYBA, CYBB, NCF1, NCF2, NCF4, and CYBC1/EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)—oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in CYBB. The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases. We investigated the clinical and molecular features of 22 Jordanian, 7 Libyan, and 2 Iraqi CGD patients from 21 different families. In addition, 11 sibling patients from these families were suspected to have been died from CGD as suggested by their familial and clinical history. All patients except 9 were children of consanguineous parents. Most of the patients suffered from AR-CGD, with mutations in CYBA, NCF1, and NCF2, encoding p22phox, p47phox, and p67phox proteins, respectively. AR-CGD was the most frequent form, in Jordan probably because consanguineous marriages are common in this country. Only one patient from non-consanguineous parents suffered from an X910 CGD subtype (0 indicates no protein expression). AR670 CGD and AR220 CGD appeared to be the most frequently found sub-types but also the most severe clinical forms compared to AR470 CGD. As a geographical clustering of 11 patients from eight Jordanian families exhibited the c.1171_1175delAAGCT mutation in NCF2, segregation analysis with nine polymorphic markers overlapping NCF2 indicates that a common ancestor has arisen ~1,075 years ago.

Published
2021
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6. Therapeutic Patient Education in Cancer Pain Management: from Practice to Research: Proposals and Strategy of the French EFFADOL Program

Author

Virith Sep Hieng, Joelle Le Garrec, Marie-Claude Ropartz, Natacha Heutte, C. Delorme, Nathalie Roux, Alexandra Leconte, Carole Van Delook, Cécile Bisson, Cyril Guillaumé, Franck Lecaer, Maryline Feuillet, Rachel Bignon, Aline Le Chevalier, Maud Gicquère, Anne-Laure Millet, Virginie Prevost, Bénédicte Clarisse, Marie-Christine Grach, Sonia Cauchin, Isabelle Lepleux, Sylvie Gehanne, Christine Le Gal, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre d’études des transformations des activités physiques et sportives (CETAPS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Aunay-Bayeux (CH Aunay-Bayeux), Réseau Régional Douleur en Basse-Normandie (RRDBN), Centre Hospitalier Robert Bisson (CH Robert Bisson), Centre Hospitalier Intercommunal Alençon-Mamers (CHICAM), Centre Hospitalier Mémorial France États-Unis de Saint-Lô (CH Saint-Lô), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Fernand-Léger d'Argentan (CH Argentan), Centre Hospitalier Jacques-Monod de Flers (CH Flers), Centre Hospitalier Public du Cotentin (CHPC), Centre Hospitalier Avranches-Granville (CH Avranches-Granville), The authors are grateful for the financial support of the Apicil Foundation and the ARDCOM (stage 1), the TAKEDA company (stage 2), the Departmental Committee of the Ligue contre le Cancer in Lower Normandy (step 4), and INCa (Invitation to tender RISP15-007_FP, stage 5)., Bodescot, Myriam, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), and CH Centre Hospitalier Public du Cotentin (CHPC)

Subjects
Research program, Biomedical Research, Pain assessment, Health Personnel, media_common.quotation_subject, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Patient Education as Topic, Nursing, Health care, Humans, Medicine, Quality (business), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030212 general & internal medicine, Program Development, Cancer pain, Brief Pain Inventory, media_common, business.industry, Public Health, Environmental and Occupational Health, Patient education, Pain management, 3. Good health, Caregivers, Oncology, 030220 oncology & carcinogenesis, General partnership, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, business
Abstract

International audience; In the field of cancer pain, therapeutic patient education (TPE) allows patients to develop skills to better manage their pain. In the Lower Normandy region of France, the management of pain is based on networking, thus allowing proximity and accessibility for all concerned. We have thus designed and initiated a broad five-stage research program that includes the following: (1) training for caregivers in TPE; (2) identifying the educational expectations of patients and their relatives with regard to cancer pain; (3) the design of a TPE program; (4) the evaluation of its quality; and (5) the evaluation of its effectiveness by comparative randomization. This article presents this approach and more particularly the research phases (stages 2, 4, 5) for which the objectives, the methodology, and the expected results are justified. Among the key points, particular attention is paid to the evaluation of the educational dimension that provides patients with self-efficacy to participate actively in the management of their pain, their perception of changes in relation to it and its impact. The choice of a specific assessment criterion (subscale 9 of the Brief Pain Inventory) and of the step-wedge design are thus argued. This approach, which is based on a partnership between health care professionals and researchers, aims to demonstrate the benefits provided by TPE to patients in order to enable them to better manage their pain on a daily basis.

Published
2017
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7. Variations in the TRPV1 gene are associated to exertional heat stroke

Author

Fabien van Coppenolle, Julien Fauré, John Rendu, Amandine Chatagnon, Nathalie Roux-Buisson, Dominique Figarella-Branger, Julie Brocard, Amandine Abriat, Laurent Pelletier, Emmanuel Sagui, Isabelle Marty, Sylvie Ducreux, C Bosson, Jacques Brocard, CCSD, Accord Elsevier, CHU Grenoble, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Grenoble Alpes (UGA), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Fondation Maladies Rares FONDATION_WES-20150602Institut National de la Sante et de la Recherche Medicale (Inserm) Association Francaise contre les Myopathies (AFM-Telethon), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Adult, Male, Candidate gene, Heat Stroke, In silico, [SDV]Life Sciences [q-bio], Mutation, Missense, TRPV1, TRPV Cation Channels, Physical Therapy, Sports Therapy and Rehabilitation, Biology, Bioinformatics, Sudden death, 03 medical and health sciences, Malignant hyperthermia, 0302 clinical medicine, Heat exhaustion, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Orthopedics and Sports Medicine, 030212 general & internal medicine, Stroke, Gene, Exome sequencing, Whole exome sequencing, Thermogenesis, 030229 sport sciences, medicine.disease, 3. Good health, In vitro contracture test, [SDV] Life Sciences [q-bio], HEK293 Cells, Military Personnel, France
Abstract

International audience; OBJECTIVES: Exertional Heat Stroke (EHS) is one of the top three causes of sudden death in athletes. Extrinsic and intrinsic risk factors have been identified but the genetic causes still remain unclear. Our aim was to identify genes responsible for EHS, which is a necessary step to identify patients at risk and prevent crises. DESIGN: Genetic and functional laboratory studies METHODS: Whole Exome Sequencing (WES) was performed to search for candidate genes in a cohort of 15 soldiers who had a documented EHS episode. In silico and in vitro functional studies were performed to evaluate the effect of mutations identified in the candidate gene TRPV1. RESULTS: WES led to the identification of two missense variations in the TRPV1 gene. These variations were very rare or unreported in control databases and located in critical domains of the protein. In vitro functional studies revealed that both variations induce a strong modification of the channel response to one of its natural agonist, the capsaicin. CONCLUSIONS: We evidenced mutations altering channel properties of the TRPV1 gene and demonstrated that TRPV1, which is involved in thermoregulation and nociception, is a new candidate gene for EHS. Our data provide the bases to explore genetic causes and molecular mechanisms governing the pathophysiology of EHS.

Published
2020
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8. Trial of labor after cesarean and contribution of pelvimetry in the prognosis of neonatal morbidity

Author

Olivier Sibony, Cécile Morin, Nathalie Roux, Diane Korb, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), and Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Adult, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Previous cesarean section, Severity of Illness Index, Infant, Newborn, Diseases, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Medicine, Humans, Retrospective Studies, 030219 obstetrics & reproductive medicine, Previous cesarean, business.industry, Vaginal delivery, Obstetrics, Cephalic presentation, Infant, Newborn, Obstetrics and Gynecology, Pelvimetry, Prognosis, Vaginal Birth after Cesarean, Trial of Labor, 3. Good health, body regions, Neonatal morbidity, Reproductive Medicine, 030220 oncology & carcinogenesis, Case-Control Studies, Observational study, Female, business
Abstract

To estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity after trial of labor after cesarean (TOLAC).Retrospective observational cases-controls study conducted at a level 3 maternity units between 2006 and 2016. Included women were patient with trial of labor after one previous cesarean section, alive singleton fetus in cephalic presentation ≥ 37WG. Two groups were compared according to pelvic mesures at pelvimetry: pelvic dimension considered as abnormal, defined by Conjugate Diameter10.5cm and/or Transverse Diameter12cm and pelvic dimension considered as normal for other women. The primary outcome was a composite criterion of neonatal morbidity and mortality. A logistic multivariate regression model was use to estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity.2474 women were included. 863 (34.8 %) have a normal pelvic dimension and 1611 (65.2 %) an abnormal. Characteristics of labor were similar in two groups. Success of TOLAC was 84.7 % in normal pelvic group and 64.6 % in abnormal dimension of pelvic group. Neonatal morbidity was similar between two groups (1.7 % in normal pelvic dimension group versus 2.3 % in abnormal pelvic dimension group, p=0.26; crude OR: 1.39 (0.77-2.49) ; adjusted OR : 0.93 (0.51-1.68)).There were no association between pelvic dimension at pelvimetry and neonatal morbidity. In case of abnormal pelvic dimension, a combination of more prudence, and stringent user practices, achieve a high rate of vaginal delivery and a neonatal morbidity comparable to the normal pelvic dimension group.

Published
2019
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9. Construction et évaluation d’un programme d’éducation thérapeutique du patient dans le domaine de la douleur liée au cancer

Author

Nathalie Roux, Maryline Feuillet, Anne-Laure Millet, Franck Lecaer, Bénédicte Clarisse, Joelle Le Garrec, Virith Sep Hieng, Marie-Claude Ropartz, Cécile Bisson, Maud Gicquère, Rachel Bignon, Virginie Prevost, Sonia Cauchin, Aline Le Chevalier, Alexandra Leconte, Carole Van Delook, Cyril Guillaumé, Marie-Christine Grach, Constance Bechet, Claire Delorme, Sylvie Gehanne, Christine Le Gal, Natacha Heutte, Isabelle Lepleux, Bodescot, Myriam, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre d’études des transformations des activités physiques et sportives (CETAPS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Aunay-Bayeux (CH Aunay-Bayeux), Réseau Régional Douleur en Basse-Normandie (RRDBN), Centre Hospitalier Robert Bisson (CH Robert Bisson), Centre Hospitalier Intercommunal Alençon-Mamers (CHICAM), Centre Hospitalier Mémorial France États-Unis de Saint-Lô (CH Saint-Lô), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Fernand-Léger d'Argentan (CH Argentan), Centre Hospitalier Jacques-Monod de Flers (CH Flers), CH Centre Hospitalier Public du Cotentin (CHPC), Centre Hospitalier Avranches-Granville (CH Avranches-Granville), Pharmacie de la Croix d'Or [Paris], Les auteurs remercient pour leur soutien financier la Fondation Apicil et l'Association ARDCOM (étape 1), la société TAKEDA (étape 2), le Comité départemental de la Ligue contre le cancer de Basse-Normandie (étape 4) et l'INCa (appel d'offres RISP15-007_FP, étape 5)., Unité de Recherche clinique [Caen], UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and Centre Hospitalier de Bayeux

Subjects
Cancer Research, Research program, Pain assessment, media_common.quotation_subject, Éducation thérapeutique du patient, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Therapeutic patient education, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Nursing, [SDV.CAN] Life Sciences [q-bio]/Cancer, Originality, Douleur liée au cancer, Gestion de la douleur, Radiology, Nuclear Medicine and imaging, Quality (business), National level, 030212 general & internal medicine, Cancer pain, Health policy, ComputingMilieux_MISCELLANEOUS, media_common, Hematology, General Medicine, Pain management, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Évaluation de la douleur, Psychology
Abstract

Pain, one of the most feared symptoms for patients with cancer, remains insufficiently alleviated and impairs quality of life. Therapeutic patient education (TPE) is a relevant approach to this problem while allowing patients to develop skills to better manage their pain. In the "Basse-Normandie" French region, the management of pain relies on two organized networks, thus allowing proximity and accessibility for all concerned. In this context, our team has begun a broad five-step research program that is part of a regional health policy: (1) training in TPE of 10 doctor/nurse pairs; (2) identification of educational expectations of patients and their relatives in the field of cancer pain; (3) design and optimization of a TPE program dedicated to cancer pain; (4) regional pilot study aiming to assess the feasibility, quality and transferability of the program; (5) evaluation of the TPE program by interventional comparative randomization at the national level. This article aims to present the program which originality and strengths are based on collaborative work between health stakeholders. Objectives, methodology and expected results of the research phase (stages 2, 4, 5) are notably developed. The main expected outcomes are to prove the effectiveness of the program in improving the knowledge and skills of patients in the field of pain cancer in order to promote their adherence to treatment and, consequently, to enable them to better manage it. The long-term objective is to disseminate the educational approach by modifying practices that provide a mutual benefit for caregivers and patients., La douleur est l'un des symptômes les plus redoutés par les patients atteints de cancer. Elle reste insuffisamment soulagée et retentit sur leur qualité de vie. L'éducation thérapeutique du patient (ETP) constitue une approche pertinente pour répondre à cette problématique en permettant au patient de développer des compétences pour mieux gérer sa douleur. En Basse-Normandie, la prise en charge de la douleur liée au cancer s'appuie notamment sur deux réseaux structurés permettant ainsi la proximité et l'accessibilité pour tous. Dans ce contexte, nous avons construit un large programme de recherche s'inscrivant dans une politique régionale de santé, en cinq étapes : (1) formation à l'ETP de 10 binômes médecins/infirmières ; (2) identification des attentes éducatives des patients et des proches dans le domaine de la douleur ; (3) conception et optimisation d'un programme ETP ; (4) étude pilote régionale permettant d'évaluer la faisabilité, la qualité et la transférabilité du programme ; (5) évaluation du programme d'ETP par randomisation comparative interventionnelle menée à l'échelle nationale. L'objectif de cet article est de présenter la stratégie de notre approche et plus particulièrement les objectifs, la méthodologie et les résultats attendus des phases de recherche (étapes 2, 4, 5). À l'issue des cinq étapes, notre ambition est de démontrer l'efficacité du programme éducatif pour améliorer les compétences des patients leur permettant de mieux gérer leur douleur. La finalité à long terme est de diffuser la démarche éducative avec une modification des pratiques apportant un bénéfice réciproque pour les soignants et les patients.

Published
2018
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10. Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: Results of a systematic screening

Author

Estelle Gandjbakhch, Julien Fauré, Françoise Hidden-Lucet, Pierre Fouret, Dagmar I. Keller, Etienne Delacrétaz, Pierre Cosnay, Nicolas Mansencal, Philippe Charron, Didier Klug, Nathalie Roux-Buisson, Erwan Donal, Fabrice Extramiana, Jonathan Trapani, Patrice Scanu, Véronique Fressart, Jean-Claude Deharo, Vincent Probst, Joël Lunardi, Robert T. Frank, Philippe Chevalier, Muscle et Pathologies, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire de Biochimie et Biologie Moléculaire, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Cardiopathies et mort subite [ERL 3147], Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Est -Lyon, Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de cardiologie et maladies vasculaires [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de Cardiologie, Hôpital de l'Ile, Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de cardiologie et de pathologie vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Cardiologie [Bâle], Hôpital Universitaire de Bâle, Assistance Publique-Hôpitaux de Paris [PHRC programme hospitalier de recherche clinique AOM05073]., Grenoble Institut des Neurosciences (GIN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Roux-Buisson, Nathalie

Subjects
Male, Proband, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Gene mutation, Ryanodine receptor 2, Electrocardiography, 0302 clinical medicine, Prevalence, Missense mutation, Prospective Studies, Arrhythmogenic Right Ventricular Dysplasia, 0303 health sciences, education.field_of_study, RYR2 gene, Desmosomes, Exons, Middle Aged, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, cardiovascular system, Cardiology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, Cardiology and Cardiovascular Medicine, Switzerland, Adult, Diagnostic Imaging, medicine.medical_specialty, Population, Catecholaminergic polymorphic ventricular tachycardia, Right ventricular cardiomyopathy, genetic testing, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], education, 030304 developmental biology, business.industry, Ryanodine Receptor Calcium Release Channel, Arrhythmogenic right ventricular dysplasia/cardiomyopathy, medicine.disease, Dysplasia, mutation, business
Abstract

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population.We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations.We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.

Published
2014
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11. Germline and somatic mosaicism for a mutation of the ryanodine receptor type 2 gene: implication for genetic counselling and patient caring

Author

Nathalie Roux-Buisson, Pascale Guicheney, Grégory Egéa, Isabelle Denjoy, Joël Lunardi, INSERM U836, équipe 4, Muscles et pathologies, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble-CHU Grenoble, CHU Grenoble, Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), and Roux-Buisson, Nathalie

Subjects
MESH: Combined Modality Therapy, MESH: Pedigree, Genetic counseling, Germline mosaicism, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Catecholaminergic polymorphic ventricular tachycardia, Genetic analysis, Ryanodine receptor 2, MESH: Defibrillators, Implantable, Germline, MESH: Ryanodine Receptor Calcium Release Channel, MESH: Nadolol, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Child, Physiology (medical), MESH: Germ-Line Mutation, medicine, Gene, MESH: Treatment Outcome, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, MESH: Humans, business.industry, medicine.disease, MESH: Male, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Mutation (genetic algorithm), cardiovascular system, MESH: Tachycardia, Ventricular, MESH: Anti-Arrhythmia Agents, MESH: Genetic Counseling, Cardiology and Cardiovascular Medicine, business, MESH: Female
Abstract

International audience; We identified a heterozygous p.Arg2401His mutation of RYR2 by sequencing the DNA of a 7-year-old girl who was referred for catecholaminergic polymorphic ventricular tachycardia (CPVT). Using high-resolution melting assay, we have demonstrated a mosaicism for this mutation in her asymptomatic mother which illustrates the benefit of extensive genetic analysis in CPVT, in particular regarding genetic counselling.

Published
2010
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12. The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands

Author

Didier Klug, Isabelle Denjoy, Antoine Leenhardt, Meiso Hayashi, Fabrice Extramiana, Miyuki Hayashi, Pascale Guicheney, Alice Maltret, Nathalie Roux-Buisson, Anne Messali, Philippe Maury, Jean-Marc Lupoglazoff, Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pediatrics Department, Nippon Medical School Hospital, Cardiology Department, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], ANTE-INSERM U836, équipe 4, Muscles et pathologies, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble-CHU Grenoble, Unité de Cardiologie Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Unité de Rythmologie et de Stimulation Cardiaque, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), French National government (PHRC no. AOR04070, P040411), Roux-Buisson, Nathalie, Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Tachycardia, Proband, Male, Pathology, Genetic testing, 030204 cardiovascular system & hematology, Ventricular tachycardia, Electrocardiography, 0302 clinical medicine, MESH : Child, Heart Rate, MESH: Child, MESH : Female, 030212 general & internal medicine, MESH: Heart Rate, Child, medicine.diagnostic_test, MESH: Adrenergic beta-Antagonists, MESH : Adult, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ventricular Premature Complexes, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Young Adult, MESH : Electrocardiography, Catecholaminergic polymorphic ventricular tachycardia, Cardiology, Female, medicine.symptom, MESH : Mutation, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH : Male, Adrenergic beta-Antagonists, MESH : Adrenergic beta-Antagonists, MESH : Young Adult, Follow-up studies, MESH : Tachycardia, Ventricular, Asymptomatic, MESH : Syncope, Syncope, 03 medical and health sciences, Young Adult, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, MESH : Adolescent, medicine, Humans, MESH : Ventricular Premature Complexes, MESH: Adolescent, MESH: Humans, Stress test, business.industry, MESH : Heart Rate, MESH : Humans, MESH: Adult, MESH: Death, Sudden, Cardiac, medicine.disease, MESH: Male, MESH: Electrocardiography, MESH: Ventricular Premature Complexes, MESH : Exercise Test, Death, Sudden, Cardiac, Bigeminy, MESH: Syncope, Mutation, Exercise Test, Tachycardia, Ventricular, MESH: Tachycardia, Ventricular, business, MESH: Exercise Test, MESH: Female, MESH : Death, Sudden, Cardiac
Abstract

International audience; AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives. METHODS AND RESULTS: The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054). CONCLUSION: In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.

Published
2012
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13. Evidence for genetic heterogeneity in Carvajal syndrome

Author

Nathalie Roux-Buisson, Rajae El Malti, Patrice Bouvagnet, Jean-Raymond Caignault, Nancy Nehme, Laboratoire Cardiogénétique, Centre de Biologie et pathologie Est, ANTE-INSERM U836, équipe 4, Muscles et pathologies, Laboratoire de Biochimie et Biologie Moléculaire, CHU Grenoble-CHU Grenoble, Service de Cardiologie et Pathologie Vasculaire, Service de Santé des Armées-Hôpital d'instruction des Armées, Desgenettes, and Roux-Buisson, Nathalie

Subjects
Male, [SDV]Life Sciences [q-bio], Cardiomyopathy, Dilated cardiomyopathy, Oligodontia, 030204 cardiovascular system & hematology, medicine.disease_cause, 030207 dermatology & venereal diseases, 0302 clinical medicine, MESH: Desmoplakins, MESH: Desmosomes, Keratoderma, Palmoplantar, Genetics, Mutation, MESH: Middle Aged, biology, Left bundle branch block, MESH: Genetic Heterogeneity, Desmosomes, Middle Aged, 3. Good health, Plakoglobin, [SDV] Life Sciences [q-bio], Hypo/oligodontia, Cardiomyopathies, Human, Cardiomyopathy, Dilated, Histology, MESH: Keratoderma, Palmoplantar, Pathology and Forensic Medicine, Genetic Heterogeneity, 03 medical and health sciences, stomatognathic system, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, Genetic heterogeneity, Desmoplakin, Cell Biology, medicine.disease, MESH: Male, Carvajal syndrome, MESH: Hair Diseases, Desmoplakins, MESH: Cardiomyopathies, biology.protein, gamma Catenin, Hair Diseases, MESH: gamma Catenin
Abstract

International audience; Carvajal syndrome is a rare syndrome with woolly hair, palmoplantar keratosis and dilated cardiomyopathy. The inheritance of the mutation is autosomal recessive. As a causal gene, the desmoplakin gene (DSP) has so far been identified; it encodes an essential component of desmosomes, a cell-cell structure aimed at keeping cells attached to each other in tissues in which cells are often exposed to strong shear forces. Recently, familial cases of an autosomal dominant Carvajal syndrome were documented with a new feature: hypo/oligodontia. A mutation in the DSP gene was also evidenced in these latter cases. A patient was seen for cardiogenetic consultation at the University Hospital of Lyon with cardiac failure involving first degree atrioventricular block, complete left bundle branch block, non-compaction of the apex of the left ventricle and a dilated cardiomyopathy. A coronarography disclosed a complete thrombosis of the right coronary artery. At examination, he had also woolly hair, mild palmoplantar keratosis and missing teeth (essentially molars and premolars). His family history was uninformative. His DNA was screened for mutations in the DSP and plakoglobin genes but no mutation could be found. This case suggests that Carvajal syndrome with hypo/oligodontia is a heterogeneous condition in which genes other than DSP might be involved, although we cannot rule out a mutation in this gene consisting in a deletion of a single exon or a gene rearrangement.

Published
2012
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14. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Author

Alain Lacampagne, Antoine Leenhardt, Julie Brocard, Nicole Monnier, Nathalie Roux-Buisson, Marine Cacheux, Julien Fauré, V. Lucet, Pierre F. Ray, Jérémy Fauconnier, Anne Fourest-Lieuvin, Isabelle Marty, Pauline Trémeaux, Isabelle Denjoy, Joël Lunardi, Philippe Mabo, Pascale Guicheney, Philippe Durand, Florence Kyndt, Vincent Probst, Hervé Le Marec, Elodie Santoni, Roux-Buisson, Nathalie, 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)-AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Biochimie et Génétique Moléculaire, 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), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, Service de Réanimation Pédiatrique et Médecine Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de rythmologie pédiatrique, Château des Côtes, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon, AGeing and IMagery (AGIM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), 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 et Génétique Moléculaire, INSERM, Association Française contre les myopathies (AFM), CNRS, Fondation Daniel Ducoin, PHRC, DRC du CHU Grenoble, Société Française de Myologie (SFM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)-Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Biochimie et Génétique Moléculaire, Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Biochimie et Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)

Subjects
Male, Muscle Proteins, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, MESH: Protein Isoforms, Endoplasmic Reticulum, Ryanodine receptor 2, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Mutant protein, MESH: Reverse Transcriptase Polymerase Chain Reaction, Chlorocebus aethiops, Missense mutation, Protein Isoforms, Myocytes, Cardiac, MESH: Animals, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Mice, Knockout, 0303 health sciences, Ryanodine receptor, Reverse Transcriptase Polymerase Chain Reaction, MESH: Genetic Predisposition to Disease, General Medicine, Articles, 3. Good health, Pedigree, MESH: COS Cells, MESH: Arrhythmias, Cardiac, MESH: Calcium, COS Cells, cardiovascular system, Female, MESH: Mutation, MESH: Rats, MESH: Pedigree, Nonsense mutation, Blotting, Western, Genes, Recessive, MESH: Carrier Proteins, Biology, Catecholaminergic polymorphic ventricular tachycardia, Sudden death, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Endoplasmic Reticulum, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Blotting, Western, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Family Health, MESH: Humans, Cell Membrane, Arrhythmias, Cardiac, MESH: Death, Sudden, Cardiac, medicine.disease, Molecular biology, MESH: Cercopithecus aethiops, MESH: Male, Rats, Death, Sudden, Cardiac, Triadin, Mutation, Tachycardia, Ventricular, MESH: Family Health, Calcium, MESH: Tachycardia, Ventricular, Carrier Proteins, MESH: Female, MESH: Cell Membrane
Abstract

International audience; Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.

Published
2012
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15. Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management

Author

Alice Goldenberg, Isabelle Denjoy, Isabelle Marty, Julien Fauré, Nathalie Roux-Buisson, Joël Lunardi, Pascale Guicheney, Gian Antonio Danieli, Laurence Faivre, John Rendu, Nadine David, Olivier Barthez, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Equipe AGIM3, Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), 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)-Laboratoire de biochimie et génétique moléculaire, CHU Grenoble-CHU Grenoble, Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Unité de cardiopédiatrie, Normandie Université (NU)-Normandie Université (NU), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de cardiologie, Department of Biology, Universita degli Studi di Padova, 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), Roux-Buisson, Nathalie, Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires [CHU Pitié-Salpétriêre], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Cardiologie [CHU de Dijon], Università degli Studi di Padova = University of Padua (Unipd), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proband, Male, Genetic counseling, RNA Splicing, CPVT, Molecular Sequence Data, Genetic Counseling, 030204 cardiovascular system & hematology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Catecholaminergic polymorphic ventricular tachycardia, medicine.disease_cause, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetics, medicine, Intronic Mutation, Calsequestrin, Humans, Family, minigene, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Base Sequence, medicine.disease, 3. Good health, Pedigree, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, RNA splicing, synonymous variations, Tachycardia, Ventricular, Female, Minigene, calsequestrin 2
Abstract

International audience; Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe arrhythmogenic disorder. Although usually transmitted in a recessive form, few cases of dominant mutations have been reported. Thirteen mutations in the CASQ2 gene have been reported so far in association with CPVT. We performed molecular analysis of the CASQ2 gene in 43 probands with CPVT and identified eight mutations in five patients. Six mutations were novel: one was a single nucleotide deletion, three affected consensus splice sites, and two had unknown consequences: the c.939 + 5G>C and the synonymous c.381C>T variations. We demonstrated that these two variations affected CASQ2 splicing using a splicing minigene assay. These data increased significantly the number of CASQ2 mutations described in association with CPVT, revealed the high prevalence of splicing and truncating mutations in this gene and brought new insight regarding the dominant inheritance of the disease. Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.Hum Mutat 32:1-5, 2011. © 2011 Wiley-Liss, Inc.

Published
2011
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16. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

Author

Philippe Charron, Guillaume Duthoit, Etienne Delacrétaz, Robert T. Frank, Catherine Coirault, Vanessa Bessirard, Guy Fontaine, Daniele Casset-Senon, François Rouzet, Yves Lecarpentier, Véronique Fressart, Didier Klug, Françoise Hidden-Lucet, Françoise Simon, Erwan Donal, Philippe Chevalier, Nathalie Roux-Buisson, Fabrice Extramiana, Olivier Dubourg, Patrice Scanu, Dagmar I. Keller, Pierre Cosnay, Bernard Hainque, Jean-Claude Deharo, Vincent Probst, Arshid Azarine, Jean-Louis Hébert, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Est -Lyon, Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Ambroise Paré [AP-HP], Service de Cardiologie, Hôpital de l'Ile, Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de cardiologie et de pathologie vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Universitaire de Bâle, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service d'Explorations Fonctionnelles Cardio-Respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de Bicêtre, Département de Radiologie Cardiovasculaire, 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), Service de Médecine Nucléaire [Tours], Service de Médecine Nucléaire [Paris 18eme], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Thérapie des maladies du muscle strié, 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), This work was supported by grants from Assistance Publique--Hôpitaux de Paris [PHRC programme hospitalier de recherche clinique AOM05073] and from INSERM [GISMR 0304]., Roux-Buisson, Nathalie, Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Chirurgie cardiaque et thoracique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Trousseau [APHP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)

Subjects
Male, Oncology, Pathology, MESH: Desmocollins, MESH: Plakophilins, DNA Mutational Analysis, Cardiomyopathy, Arrhythmogenic right ventricular dysplasia, 030204 cardiovascular system & hematology, medicine.disease_cause, Gene, MESH: Genotype, 0302 clinical medicine, MESH: Desmoplakins, MESH: Desmosomes, Diagnosis, MESH: DNA Mutational Analysis, 0303 health sciences, Mutation, Desmoglein 2, MESH: Middle Aged, medicine.diagnostic_test, MESH: Genetic Testing, MESH: Genetic Predisposition to Disease, Desmosome, Desmosomes, Middle Aged, Prognosis, 3. Good health, MESH: Arrhythmias, Cardiac, MESH: Young Adult, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Genotype, Desmoglein-2, Context (language use), Sudden death, MESH: Prognosis, Young Adult, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Arrhythmogenic Right Ventricular Dysplasia, 030304 developmental biology, Genetic testing, Desmocollins, DSC2, MESH: Humans, business.industry, Arrhythmias, Cardiac, MESH: Adult, medicine.disease, MESH: Male, Desmoplakins, gamma Catenin, business, Plakophilins, MESH: Female, MESH: Desmoglein 2
Abstract

International audience; AIMS: Five desmosomal genes have been recently implicated in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) but the clinical impact of genetics remains poorly understood. We wanted to address the potential impact of genotyping. METHODS AND RESULTS: Direct sequencing of the five genes (JUP, DSP, PKP2, DSG2, and DSC2) was performed in 135 unrelated patients with ARVD/C. We identified 41 different disease-causing mutations, including 28 novel ones, in 62 patients (46%). In addition, a genetic variant of unknown significance was identified in nine additional patients (7%). Distribution of genes was 31% (PKP2), 10% (DSG2), 4.5% (DSP), 1.5% (DSC2), and 0% (JUP). The presence of desmosomal mutations was not associated with familial context but was associated with young age, symptoms, electrical substrate, and extensive structural damage. When compared with other genes, DSG2 mutations were associated with more frequent left ventricular involvement (P = 0.006). Finally, complex genetic status with multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (P = 0.047). CONCLUSION: This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.

Published
2010
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17. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia

Author

Alice Maltret, Anne Messali, Pascale Guicheney, Joël Kamblock, Joël Lunardi, Antoine Leenhardt, Fabrice Extramiana, Meiso Hayashi, Elisabeth Villain, Didier Klug, Seiji Takatsuki, Nathalie Roux Buisson, Isabelle Denjoy, Jean Marc Lupoglazoff, Miyuki Hayashi, Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biochimie et Génétique Moléculaire, CHU Grenoble, Unité de Cardiologie Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Cardiologie du Taaone, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors received a grant from the French national government named Programme Hospitalier de Recherche Clinique No. AOR04070, P040411., Roux-Buisson, Nathalie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Male, Heart disease, Ventricular tachycardia, tachycardia, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, MESH : Child, MESH: Child, MESH: Incidence, Child, MESH: Middle Aged, Incidence, Hazard ratio, MESH: Follow-Up Studies, MESH : Incidence, 3. Good health, ventricular, MESH: Young Adult, Child, Preschool, beta-blocker, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, MESH : Young Adult, MESH : Syncope, Syncope, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Adolescent, Physiology (medical), death, MESH: Polymorphism, Genetic, MESH: Calsequestrin, Humans, MESH : Middle Aged, Risk factor, Beta blocker, sudden, MESH: Adolescent, Polymorphism, Genetic, MESH: Humans, MESH : Humans, MESH: Child, Preschool, MESH : Follow-Up Studies, MESH: Adult, medicine.disease, Death, Sudden, Cardiac, MESH: Family Health, MESH: Tachycardia, Ventricular, mutation, MESH: Exercise Test, MESH: Female, clinical genetics, Tachycardia, MESH : Polymorphism, Genetic, Kaplan-Meier Estimate, MESH : Child, Preschool, 030204 cardiovascular system & hematology, Sudden cardiac death, Risk Factors, MESH: Risk Factors, MESH : Female, 030212 general & internal medicine, MESH: Kaplan-Meiers Estimate, MESH : Ryanodine Receptor Calcium Release Channel, MESH: Adrenergic beta-Antagonists, Middle Aged, MESH : Adult, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Calsequestrin, MESH : Risk Factors, follow-up studies, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiology, Female, medicine.symptom, Adult, Adolescent, medicine.drug_class, MESH : Male, Adrenergic beta-Antagonists, MESH : Adrenergic beta-Antagonists, MESH : Tachycardia, Ventricular, MESH : Family Health, Catecholaminergic polymorphic ventricular tachycardia, Young Adult, Internal medicine, medicine, Calsequestrin, Family Health, business.industry, Ryanodine Receptor Calcium Release Channel, MESH : Kaplan-Meiers Estimate, MESH: Death, Sudden, Cardiac, MESH: Male, MESH : Exercise Test, MESH: Syncope, Exercise Test, Tachycardia, Ventricular, business, MESH : Death, Sudden, Cardiac
Abstract

Background— The pathophysiological background of catecholaminergic polymorphic ventricular tachycardia is well understood, but the clinical features of this stress-induced arrhythmic disorder, especially the incidence and risk factors of arrhythmic events, have not been fully ascertained. Methods and Results— The outcome in 101 catecholaminergic polymorphic ventricular tachycardia patients, including 50 probands, was analyzed. During a mean follow-up of 7.9 years, cardiac events defined as syncope, aborted cardiac arrest, including appropriate discharges from implantable defibrillators, or sudden cardiac death occurred in 27 patients, including 2 mutation carriers with normal exercise tests. The estimated 8-year event rate was 32% in the total population and 27% and 58% in the patients with and without β-blockers, respectively. Absence of β-blockers (hazard ratio [HR], 5.48; 95% CI, 1.80 to 16.68) and younger age at diagnosis (HR, 0.54 per decade; 95% CI, 0.33 to 0.89) were independent predictors. Fatal or near-fatal events defined as aborted cardiac arrest or sudden cardiac death occurred in 13 patients, resulting in an estimated 8-year event rate of 13%. Absence of β-blockers (HR, 5.54; 95% CI, 1.17 to 26.15) and history of aborted cardiac arrest (HR, 13.01; 95% CI, 2.48 to 68.21) were independent predictors. No difference was observed in cardiac and fatal or near-fatal event rates between probands and family members. Conclusions— Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia probands and affected family members during the long-term follow-up, even while taking β-blockers, which was associated with a lower event rate. Further studies evaluating concomitant therapies are necessary to improve outcome in these patients.

Published
2009
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18. Identification of the First Mutations in the Human Triadin Gene, Associated to Catecholaminergic Tachycardia, a Pathology of the Cardiac Calcium Release Complex

Author

Julie Brocard, Joël Lunardi, Nathalie Roux-Buisson, Isabelle Marty, Alain Lacampagne, Julien Fauré, Marine Cacheux, Jérémy Fauconnier, and Anne Fourest-Lieuvin

Subjects
Candidate gene, Pathology, medicine.medical_specialty, genetic structures, Biophysics, chemistry.chemical_element, Calcium, Biology, Calsequestrin, Catecholaminergic polymorphic ventricular tachycardia, Ryanodine receptor 2, Calcium in biology, 03 medical and health sciences, 0302 clinical medicine, medicine, 030304 developmental biology, 0303 health sciences, Ryanodine receptor, musculoskeletal system, medicine.disease, eye diseases, 3. Good health, stomatognathic diseases, Triadin, chemistry, cardiovascular system, sense organs, 030217 neurology & neurosurgery
Abstract

Cardiac contraction is triggered when a membrane depolarisation induces a massive increase in intracellular calcium concentration. This process called “excitation-contraction (E-C) coupling” relies on a multimolecular protein complex, the calcium release complex (CRC) organized around the sarcoplasmic reticulum calcium channel, the ryanodine receptor (RyR2). Among the proteins involved in the efficient function of the CRC, calsequestrin, triadin and junctin are sarcoplasmic reticulum proteins able to interact with RyR2 and regulate calcium release.Mutations in RyR2 and calsequestrin are associated to a rare but fatal cardiac arrhythmia: catecholaminergic polymorphic ventricular tachycardia (CPVT). Nevertheless, variations in these two genes (RYR2 and CASQ2) account so far for only 50 to 70% of the cases, suggesting that other genes are most probably involved. To reveal new genes involved in CPVT, we have based a candidate gene approach on the hypothesis that the pathology could be considered as a disease of the calcium release complex. We therefore searched for variations in the genes encoding proteins of the CRC in a large French cohort of CPVT patients with no detected mutations in RYR2 or CASQ2. We have identified for the first time mutations in the human triadin gene TRDN, and studied the functional consequences of a missense mutation both in a cell model and in vivo after expression in triadin KO mice. Our results confirmed the hypothesis that CPVT can be more generally considered as a defect in the CRC.

Published
2012
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