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2. Whole genome sequencing identifies a homozygous splicing variant in TDRKH segregating with non‐obstructive azoospermia in an Iranian family.

Author

Amiri‐Yekta, Amir, Sen, Sharanya, Hazane‐Puch, Florence, Tebbakh, Célia, Roux‐Buisson, Nathalie, Cazin, Caroline, Thierry‐Mieg, Nicolas, Bouras, Ahmed, Mohammad Ali, Sadighi‐Gilani, Hosseini, Seyedeh‐Hanieh, Goodarzian, Maedeh, Gourabi, Hamid, Ray, Pierre F., and Kherraf, Zine‐Eddine

Subjects
AZOOSPERMIA, WHOLE genome sequencing, GERM cells, KNOCKOUT mice, GENETIC testing
Abstract

Non‐obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic options are very limited. Beyond their diagnostic value, genetic tests for NOA also hold prognostic potential. Specifically, genetic diagnosis enables the establishment of genotype‐testicular phenotype correlations, which, in some cases, provide a negative predictive value for testicular sperm extraction (TESE), thereby preventing unnecessary surgical procedures. In this study, we employed whole‐genome sequencing (WGS) to investigate two generations of an Iranian family with NOA and identified a homozygous splicing variant in TDRKH (NM_001083965.2: c.562‐2A>T). TDRKH encodes a conserved mitochondrial membrane‐anchored factor essential for piRNA biogenesis in germ cells. In Tdrkh knockout mice, de‐repression of retrotransposons in germ cells leads to spermatogenic arrest and male infertility. Previously, our team reported TDRKH involvement in human NOA cases through the investigation of a North African cohort. This current study marks the second report of TDRKH's role in NOA and human male infertility, underscoring the significance of the piRNA pathway in spermatogenesis. Furthermore, across both studies, we demonstrated that men carrying TDRKH variants, similar to knockout mice, exhibit complete spermatogenic arrest, correlating with failed testicular sperm retrieval. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: Results of a systematic screening

Author

Roux-Buisson, Nathalie, Gandjbakhch, Estelle, Donal, Erwan, Probst, Vincent, Deharo, Jean-Claude, Chevalier, Philippe, Klug, Didier, Mansencal, Nicolas, Delacretaz, Etienne, Cosnay, Pierre, Scanu, Patrice, Extramiana, Fabrice, Keller, Dagmar, Hidden-Lucet, Françoise, Trapani, Jonathan, Fouret, Pierre, Frank, Robert, Fressart, Veronique, Fauré, Julien, Lunardi, Joel, and Charron, Philippe

Published
2014
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7. Liste des auteurs

Author

Baudin, Florent, Alaoui, Myriem Belghiti, Bordes-Demolis, Maryline, Bourdaud, Nathalie, Brackhahn, Michael, Brebion, Myriam, Bruneau, Béatrice, Caruselli, Marco, Cercueil, Éloïse, Colas, Anne-Emmanuelle, Constant, Isabelle, Dadure, Christophe, Dahmani, Souhayl, Dalmas-Laurent, Anne-Frédérique, de Cock, Adrien, Siqueira, Mathilde De Queiroz, Devys, Jean-Michel, Evain, Jean-Noël, Gall, Olivier, Galland, Anne, France, Groupe H.M., Keita, Hawa, Kern, Delphine, Laffargue, Anne, Larcher, Claire, Lejus-Bourdeau, Corinne, Lenoire, Alexandre, Loreau, Chine, Julien-Marsollier, Florence, Michel, Fabrice, Montmayeur, Juliette, Morin, Valérie, Nouette-Gaulain, Karine, Pico, Julien, Repessé, Xavier, Roux-Buisson, Nathalie, Sabourdin, Nada, Salaun, Jean-Philippe, Salvi, Nadège, Sola, Chrystelle, Vergnaud, Estelle, and Veyckemans, Francis

Published
2024
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8. Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome

Author

Le Tanno, Pauline, primary, Folacci, Mathilde, additional, Revilloud, Jean, additional, Faivre, Laurence, additional, Laurent, Gabriel, additional, Pinson, Lucile, additional, Amedro, Pascal, additional, Millat, Gilles, additional, Janin, Alexandre, additional, Vivaudou, Michel, additional, Roux-Buisson, Nathalie, additional, and Fauré, Julien, additional

Published
2021
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9. 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 mutations

Author

Maltret, Alice, primary, Benaich, Fatima Azzahrae, additional, Rendu, John, additional, Fressart, Véronique, additional, Roux-Buisson, Nathalie, additional, Bonnet, Damien, additional, and Denjoy, Isabelle, additional

Published
2021
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11. A Type 2 Ryanodine Receptor Variant in the Helical Domain 2 Associated with an Impairment of the Adrenergic Response

Author

Blancard, Malorie, Touat-Hamici, Zahia, Aguilar-Sanchez, Yuriana, Yin, Liheng, Vaksmann, Guy, Roux-Buisson, Nathalie, Fressart, Véronique, Denjoy, Isabelle, Klug, Didier, Neyroud, Nathalie, Ramos-Franco, Josefina, Gomez, Ana Maria, Guicheney, Pascale, Gestionnaire, HAL Sorbonne Université 5, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Rush University Medical Center [Chicago], Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Ramsay Générale de Santé - Hôpital Privé La Louvière, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, 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), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Signalisation et physiopathologie cardiovasculaire (UMRS1180), 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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Neyroud, Nathalie, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Grenoble Institut des Neurosciences (GIN), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
calcium, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, adrenergic stimulation, CPVT, cardiovascular system, Medicine, RYR2, sudden death, arrhythmia, Article, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is RYR2, encoding the cardiac ryanodine receptor (RyR2). We report a novel RYR2 variant, p.Asp3291Val, outside the four CPVT mutation hotspots, in three CPVT families with numerous sudden deaths. This missense variant was first identified in a four-generation family, where eight sudden cardiac deaths occurred before the age of 30 in the context of adrenergic stress. All affected subjects harbored at least one copy of the RYR2 variant. Three affected sisters were homozygous for the variant. The same variant was found in two additional CPVT families. It is located in the helical domain 2 and changes a negatively charged amino acid widely conserved through evolution. Functional analysis of D3291V channels revealed a normal response to cytosolic Ca2+, a markedly reduced luminal Ca2+ sensitivity and, more importantly, an absence of normal response to 8-bromo-cAMP and forskolin stimulation in both transfected HEK293 and HL-1 cells. Our data support that the D3291V-RyR2 is a loss-of-function RyR2 variant responsible for an atypical form of CPVT inducing a mild dysfunction in basal conditions but leading potentially to fatal events through its unresponsiveness to adrenergic stimulation.

Published
2021
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13. 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

Bakri, Faris Ghalib, primary, Mollin, Michelle, additional, Beaumel, Sylvain, additional, Vigne, Bénédicte, additional, Roux-Buisson, Nathalie, additional, Al-Wahadneh, Adel Mohammed, additional, Alzyoud, Raed Mohammed, additional, Hayajneh, Wail Ahmad, additional, Daoud, Ammar Khaled, additional, Shukair, Mohammed Elian Abu, additional, Karadshe, Mansour Fuad, additional, Sarhan, Mahmoud Mohammad, additional, Al-Ramahi, Jamal Ahmad Wadi, additional, Fauré, Julien, additional, Rendu, John, additional, and Stasia, Marie Jose, additional

Published
2021
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15. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Author

Roux-Buisson, Nathalie, Cacheux, Marine, Fourest-Lieuvin, Anne, Fauconnier, Jeremy, Brocard, Julie, Denjoy, Isabelle, Durand, Philippe, Guicheney, Pascale, Kyndt, Florence, Leenhardt, Antoine, Le Marec, Hervé, Lucet, Vincent, Mabo, Philippe, Probst, Vincent, Monnier, Nicole, Ray, Pierre F., Santoni, Elodie, Trémeaux, Pauline, Lacampagne, Alain, Fauré, Julien, Lunardi, Joël, and Marty, Isabelle

Published
2012
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18. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

Author

Fressart, Veronique, Duthoit, Guillaume, Donal, Erwan, Probst, Vincent, Deharo, Jean-Claude, Chevalier, Philippe, Klug, Didier, Dubourg, Olivier, Delacretaz, Etienne, Cosnay, Pierre, Scanu, Patrice, Extramiana, Fabrice, Keller, Dagmar, Hidden-Lucet, Françoise, Simon, Françoise, Bessirard, Vanessa, Roux-Buisson, Nathalie, Hebert, Jean-Louis, Azarine, Arshid, Casset-Senon, Daniele, Rouzet, François, Lecarpentier, Yves, Fontaine, Guy, Coirault, Catherine, Frank, Robert, Hainque, Bernard, and Charron, Philippe

Published
2010
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20. International Triadin Knockout Syndrome Registry

Author

Clemens, Daniel J., primary, Tester, David J., additional, Giudicessi, John R., additional, Bos, J. Martijn, additional, Rohatgi, Ram K., additional, Abrams, Dominic J., additional, Balaji, Seshadri, additional, Crotti, Lia, additional, Faure, Julien, additional, Napolitano, Carlo, additional, Priori, Silvia G., additional, Probst, Vincent, additional, Rooryck-Thambo, Caroline, additional, Roux-Buisson, Nathalie, additional, Sacher, Frederic, additional, Schwartz, Peter J., additional, Silka, Michael J., additional, Walsh, Mark A., additional, and Ackerman, Michael J., additional

Published
2019
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22. Research and characterization of genes implicated in the catecholaminergic ventricular tachycardia

Author

Roux-Buisson, Nathalie, STAR, ABES, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Grenoble, and Joël Lunardi

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Triadin, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, CPVT, Mutation, Triadine, Arythmies, TVPC, Functional study, Heart, Arrhythmias, Étude fonctionnelle, Coeur
Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe inherited arrhythmogenic disorder, responsible for sudden death in young patients. It is a genetically heterogenous pathology with an autosomal dominant form associated with mutations of the RYR2 gene, and a recessive form associated with mutations of the CASQ2 gene. The ryanodine receptor RyR2 is a Ca2+ channel, and the calsequestrin Casq2 is the major calcium storage protein, located in the sarcoplasmic reticulum of the cardiomyocytes. They belong to the calcium release complex (CRC) that plays a central role in excitation-contraction coupling. In this work, we report the identification of RYR2 and CASQ2 mutations in 75 and 11 CPVT probands, respectively. We identified two cases of germline and somatic mosaicism in RYR2. Two splicing mutations of CASQ2 have been validated using a splicing minigene assay. We searched for mutations among 97 CPVT probands, negative for RYR2 and CASQ2, in three candidate genes: TRDN, ASPH and FKBP1B, encoding three proteins of the CRC. We did not identify any mutation of ASPH and FKBP1B genes. However, we found three mutations in the TRDN gene, encoding the cardiac triadin: a microdeletion, a nonsense mutation, both leading to a premature stop codon, and a missense mutation. We demonstrated that the missense mutation induces a drastic reduction of the protein in cellular and animal models. All the three mutations would thus be associated with the absence of triadin, leading to dysfunction of the CRC, and arythmias. In conclusion, our results confirm that RYR2 is the major gene implicated in CPVT, and CASQ2 rarely implicated. Moreover, we report mutations of the TRDN gene for the first time in pathology, as a third gene associated with a rare autosomal recessive form of CPVT., La Tachycardie Ventriculaire Polymorphe Catécholaminergique (TVPC) est une pathologie rythmique héréditaire rare et sévère, responsable de mort subite chez le sujet jeune. Les mutations des gènes RYR2 et CASQ2 sont associées respectivement à une transmission autosomique dominante et récessive de la maladie. Le canal calcique RyR2 et la protéine chélatrice du calcium Casq2 sont situés dans le réticulum sarcoplasmique (RS) où ils participent au complexe de relâchement calcique (CRC), essentiel à l'homéostasie calcique cardiaque. L'analyse de RYR2 et CASQ2 chez 214 probands ayant présenté une TVPC nous a permis d'identifier respectivement des mutations chez 75 et 11 probands. Deux cas de mosaïques germinales et somatiques ont été identifiés dans le gène RYR2. Deux mutations d'épissage du gène CASQ2 ont été validées à l'aide de minigènes. Chez 97 patients négatifs pour RYR2 et CASQ2, nous avons décidé de rechercher des mutations de trois protéines du CRC (la triadine, la junctine et FKBP12.6) en séquençant les gènes correspondants. Nous n'avons retrouvé aucune mutation de la junctine, ni de FKBP12.6. En revanche, nous avons identifié trois mutations de la triadine: une micro-délétion et une mutation non-sens entraînant un codon stop prématuré, ainsi qu'une variation faux-sens, dont la caractérisation à l'aide de modèle animal et cellulaire a montré qu'elle entraînait une dégradation massive de la protéine. Les mutations du gène TRDN seraient associées à une absence de triadine entraînant une dysfonction du CRC, à l'origine des arythmies observées. En conclusion, nos résultats confirment que RYR2 est le gène majeur impliqué dans la TVPC, CASQ2 étant rarement impliqué; et nous rapportons, pour la première fois, des mutations du gène TRDN en pathologie humaine, associée à une forme autosomique rare de TVPC.

Published
2012

23. Functional Characterization of a Central Core Disease RyR1 Mutation (p.Y4864H) Associated with Quantitative Defect in RyR1 Protein

Author

Cacheux, Marine, primary, Blum, Ariane, additional, Sébastien, Muriel, additional, Wozny, Anne Sophie, additional, Brocard, Julie, additional, Mamchaoui, Kamel, additional, Mouly, Vincent, additional, Roux-Buisson, Nathalie, additional, Rendu, John, additional, Monnier, Nicole, additional, Krivosic, Renée, additional, Allen, Paul, additional, Lacour, Arnaud, additional, Lunardi, Joël, additional, Fauré, Julien, additional, and Marty, Isabelle, additional

Published
2015
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25. Exon Skipping as a Therapeutic Strategy Applied to anRYR1Mutation with Pseudo-Exon Inclusion Causing a Severe Core Myopathy

Author

Rendu, John, primary, Brocard, Julie, additional, Denarier, Eric, additional, Monnier, Nicole, additional, Piétri-Rouxel, France, additional, Beley, Cyriaque, additional, Roux-Buisson, Nathalie, additional, Gilbert-Dussardier, Brigitte, additional, Perez, Marie José, additional, Romero, Norma, additional, Garcia, Luis, additional, Lunardi, Joël, additional, Fauré, Julien, additional, Fourest-Lieuvin, Anne, additional, and Marty, Isabelle, additional

Published
2013
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29. 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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30. Delineation of the 3p14.1p13 microdeletion associated with syndromic distal limb contractures

Author

Michel Francoise, Patrick Callier, Steven A. Vokes, Susanne Kjaergaard, Laurence Duplomb, Thomas Lee Dahm, Julien Thevenon, Nicole Monnier, Marie Hélène Aubriot-Lorton, Frédéric Huet, Tara Montgomery, Haley O. Tucker, Clémence Ragon, Nathalie Marle, Katherine Neas, Francine Mugneret, Pierre-Simon Jouk, Joël Lunardi, Klaus Dieterich, Laurence Faivre, Christel Thauvin-Robinet, Anne Laure Mosca-Boidron, Joanne Dixon, 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 ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Laboratoire de cytogénétique (CHU de Dijon), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Service de pédiatrie, Centre Hospitalier Wiliam Morey, Northern Genetics Service, Newcastle University [Newcastle], Department of Clinical Genetic, Rigshospitalet [Copenhagen], Central and Southern Regional Genetic Services, Wellington Hospital Private, Department of Pediatrics, Nordsjællands Hospital - Hillerød, Service de pédiatrie (CHU de Dijon), Service de Pathologie [CHU de Dijon], Section of Molecular Cell & Developmental Biology, Institute for Cellular and Molecular Biology-University of Texas at Austin [Austin], Graduate Program in Cell and Molecular Biology, University of Texas at Austin [Austin], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Chalon-sur-Saône William Morey, Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, University of Texas at Austin [Austin]- Institute for Cellular and Molecular Biology, and Roux-Buisson, Nathalie

Subjects
Male, Pathology, medicine.medical_specialty, Contracture, [SDV]Life Sciences [q-bio], Locus (genetics), FOXP1, Biology, Mice, distal limb contractures, symbols.namesake, Exon, EIF4E3, Intellectual disability, Genetics, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 3p141p13 microdeletion, Genetics (clinical), Arthrogryposis, Chromosome Aberrations, Mice, Knockout, Sanger sequencing, Comparative Genomic Hybridization, [ SDV ] Life Sciences [q-bio], Extremities, Forkhead Transcription Factors, Syndrome, Microdeletion syndrome, medicine.disease, Blepharophimosis, Phenotype, Repressor Proteins, [SDV] Life Sciences [q-bio], array-CGH, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], symbols, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chromosomes, Human, Pair 3, France, Carrier Proteins, intronic regulatory sequence
Abstract

International audience; Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20–25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 micro-deletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.

Published
2014
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31. Trisk 32 regulates IP3 receptors in rat skeletal myoblasts

Author

Tamás Oláh, Olga Ruzsnavszky, Isabelle Marty, Sarah Oddoux, László Csernoch, János Fodor, Roux-Buisson, Nathalie, Department of Physiology, University of Debrecen Egyetem [Debrecen], 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), Hungarian National Science Fund (OTKA) K75604 NK78398, Association Francaise contre les Myopathies (AFM), and University of Debrecen

Subjects
Vasopressin, Physiology, Clinical Biochemistry, Skeletal muscle, Muscle Proteins, Stimulation, Biológiai tudományok, MESH: Protein Isoforms, MESH: Ryanodine Receptor Calcium Release Channel, Myoblasts, chemistry.chemical_compound, 0302 clinical medicine, Természettudományok, Calcium transient, Inositol 1,4,5-Trisphosphate Receptors, Protein Isoforms, Myocyte, MESH: Animals, Receptor, Excitation Contraction Coupling, MESH: Myoblasts, Skeletal, 0303 health sciences, 5-trisphosphate, Ryanodine receptor, Intracellular Signaling Peptides and Proteins, medicine.anatomical_structure, MESH: Calcium, MESH: Vasopressins, medicine.medical_specialty, MESH: Rats, Vasopressins, Myoblasts, Skeletal, Bradykinin, MESH: Carrier Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Calcium Signaling, MESH: Muscle Proteins, 03 medical and health sciences, MESH: Inositol 1,4,5-Trisphosphate Receptors, MESH: Excitation Contraction Coupling, Physiology (medical), Internal medicine, medicine, Extracellular, Animals, Calcium Signaling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, MESH: Bradykinin, Ryanodine Receptor Calcium Release Channel, Inositol 1, Rats, Endocrinology, chemistry, Calcium, Carrier Proteins, Endoplasmic reticulum, 030217 neurology & neurosurgery
Abstract

International audience; To date, four isoforms of triadins have been identified in rat skeletal muscle. While the function of the 95-kDa isoform in excitation-contraction coupling has been studied in detail, the role of the 32-kDa isoform (Trisk 32) remains elusive. Here, Trisk 32 overexpression was carried out by stable transfection in L6.G8 myoblasts. Co-localization of Trisk 32 and IP(3) receptors (IP(3)R) was demonstrated by immunocytochemistry, and their association was shown by co-immunoprecipitation. Functional effects of Trisk 32 on IP(3)-mediated Ca(2+) release were assessed by measuring changes in [Ca(2+)](i) following the stimulation by bradykinin or vasopressin. The amplitude of the Ca(2+) transients evoked by 20 μM bradykinin was significantly higher in Trisk 32-overexpressing (p < 0.01; 426 ± 84 nM, n = 27) as compared to control cells (76 ± 12 nM, n = 23). The difference remained significant (p < 0.02; 217 ± 41 nM, n = 21, and 97 ± 29 nM, n = 31, respectively) in the absence of extracellular Ca(2+). Similar observations were made when 0.1 μM vasopressin was used to initiate Ca(2+) release. Possible involvement of the ryanodine receptors (RyR) in these processes was excluded, after functional and biochemical experiments. Furthermore, Trisk 32 overexpression had no effect on store-operated Ca(2+) entry, despite a decrease in the expression of STIM1. These results suggest that neither the increased activity of RyR, nor the amplification of SOCE, is responsible for the differences observed in bradykinin- or vasopressin-evoked Ca(2+) transients; rather, they were due to the enhanced activity of IP(3)R. Thus, Trisk 32 not only co-localizes with, but directly contributes to, the regulation of Ca(2+) release via IP(3)R.

Published
2011
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32. From lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes

Author

Anne Blanchard, Joël Lunardi, Haifa Hichri, Rémi Salomon, Michel Remesy, Rosa Vargas Poussou, Geneviève Baujat, Nicole Monnier, Charles Coutton, Bruno Ranchin, Véronique Satre, Olivier Dorseuil, John Rendu, François Nobili, Biochimie et Genetique Moleculaire, CHU Grenoble, Laboratoire de Genetique Chromosomique, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dpt de Genetique, Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre d'Investigation Clinique, Service de nephrologie pédiatrique, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Centre de Référence des Maladies Rénales Rares, Hospices Civil de Lyon, Service de Nephrologie, CHU Toulouse [Toulouse], Service de néphrologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, [Institut Cochin] Département Développement, Reproduction et Cancer ( DRC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Laboratoire de Génétique Chromosomique [CHU de Grenoble], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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, 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, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence des Maladies Rénales Héréditaires de l'enfant et de l'adulte, Agence National de la Recherche, GIS-Maladies Rares, Association du Syndrome de Lowe and Fondation Daniel Ducoin, R.V.-P. and A.B. are supported by EUNEFRON (FP7, GA]201590) programs of the R.V.-P. and A.B. are supported by EUNEFRON (FP7, GA#201590) programs of the European Community., European Project: 201590,EC:FP7:HEALTH,FP7-HEALTH-2007-A,EUNEFRON(2008), Service Néphrologie, médecine interne et hypertension pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Roux-Buisson, Nathalie, and European Network for the Study of Orphan Nephropathies - EUNEFRON - - EC:FP7:HEALTH2008-05-01 - 2012-04-30 - 201590 - VALID

Subjects
Male, MESH: Dent Disease, MESH: Mutation, Oculocerebrorenal syndrome, DNA Mutational Analysis, Nonsense mutation, 030232 urology & nephrology, Dent Disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Protein degradation, Biology, MESH: Phenotype, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Chloride Channels, Genetics, medicine, Humans, Missense mutation, RNA, Messenger, MESH: DNA Mutational Analysis, Genetics (clinical), MESH: RNA, Messenger, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Mutation, MESH: Humans, MESH: Chloride Channels, Life Sciences, medicine.disease, Phosphoric Monoester Hydrolases, MESH: Male, 3. Good health, Oculocerebrorenal Syndrome, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phosphoric Monoester Hydrolases, OCRL, MESH: Oculocerebrorenal Syndrome
Abstract

International audience; Mutations of OCRL1 are associated with both the oculocerebrorenal syndrome Lowe, a multi-systemic and Dent-2 disease, a renal tubulopathy. We have identified a mutation in 130 Lowe syndrome families and 6 affected by Dent-2 disease with 51 of these mutations being novel. No founding effect was evidenced for recurrent mutations. Two mutations initially reported as causing Dent-2 disease were identified in patients, including two brothers, presenting with Lowe syndrome thus extending the clinical variability of OCRL1 mutations. mRNA levels, protein content and PiP2-ase activities were analyzed in patient's fibroblasts. Although mRNA levels were normal in cells harbouring a missense mutation, the OCRL1 content was markedly lowered suggesting that enzymatic deficiency resulted mainly from protein degradation rather than a catalytic inactivation as usually reported. Analysis of a splicing mutation that led to the elimination of the initiation codon evidenced the presence of shortened forms of OCRL1 that might result from the use of alternative initiation codons. The specific mapping of the frameshift and nonsense mutations, exclusively identified in exons 1-7 and exons 8-23 respectively for Dent disease and Lowe syndrome together with the possible use of alternative initiation codons might be related to their clinical expression i.e. Lowe syndrome or Dent-2 disease.

Published
2011
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33. A Recurrent Deletion of DPY19L2 Causes Infertility in Man by Blocking Sperm Head Elongation and Acrosome Formation

Author

Marrakchi Ouafi, Isabelle Koscinski, Ghaya Merdassi, B. Sèle, Fethi Zhioua, François Vialard, Stéphane Viville, Raoudha Zouari, Thérèse Schweitzer, Mariem Ben Khelifa, Radu Harbuz, Mounir Makni, Lazhar Halouani, Charles Coutton, Christophe Arnoult, Nathalie Sermondade, Pierre-Simon Jouk, Amel Zhioua, Virginie Pierre, Véronique Satre, Mahmoud Kharouf, Jessica Escoffier, Chema Triki, Yorgos Nikas, Pierre F. Ray, Habib Latrous, Sylviane Hennebicq, Joël Lunardi, Farid Abada, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), 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), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Clinique de la reproduction les Jasmins, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Procréation médicalement Assistée, hôpital Aziza Othmana, Athens Innovative Microscopy, Département de Biologie de la Reproduction, CHI Poissy-Saint-Germain, Service de Biologie de la Reproduction, CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), entre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), Histologie Embriologie Cytogénétique CECOS, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'assistance médicale à la procréation, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Rhône-Alpes Region - CIBLE 2009 program, Roux-Buisson, Nathalie, 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), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], and Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]

Subjects
Male, Infertility, DNA Copy Number Variations, Genetic Linkage, Non-allelic homologous recombination, Reproductive technology, Biology, Male infertility, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Report, Genetics, medicine, Homologous chromosome, Humans, Genetics(clinical), Family, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Acrosome, Infertility, Male, Genetics (clinical), Globozoospermia, 030304 developmental biology, 0303 health sciences, Jordan, 030219 obstetrics & reproductive medicine, Homozygote, Membrane Proteins, medicine.disease, Pedigree, 3. Good health, Genetic Loci, Sperm Head, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gene Deletion
Abstract

International audience; An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.

Published
2011
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34. Brachytelephalangic Chondrodysplasia Punctata: Prenatal Diagnosis and Postnatal Outcome

Author

Stéphanie Boulet, Pierre-Simon Jouk, Claudia Durand, Catherine Charra, Marc Althuser, Klaus Dieterich, Jean-Patrick Schaal, Frédérique Nugues, Maternité, Hôpital Chambéry, Clinique de génétique, CHU Grenoble, Centre de diagnostic prénatal, Gynécologue - Obstétricien, Médecin libéral, Clinic of Gynecology and Obstetrics, University Hospital, Grenoble, France, and Roux-Buisson, Nathalie

Subjects
Male, Embryology, Pathology, MESH: Maxilla, MESH: Amniocentesis, MESH: Pregnancy, Pregnancy, Binder phenotype, Prenatal Diagnosis, Maxilla, Chondrodysplasia punctata, Maxillofacial Development, Arylsulfatase E, Arylsulfatases, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Pregnancy Outcome, MESH: Nose, MESH: Ultrasonography, Prenatal, Obstetrics and Gynecology, Genetic Diseases, X-Linked, General Medicine, MESH: Maxillofacial Abnormalities, Hypoplasia, Maxillofacial Abnormalities, 3. Good health, Bone dysplasia, Amniocentesis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Face, musculoskeletal diseases, Chondrodysplasia Punctata, medicine.medical_specialty, Mutation, Missense, Prenatal diagnosis, Nose, Ultrasonography, Prenatal, Brachytelephalangy, 03 medical and health sciences, Peroxisomal disorder, MESH: Genetic Diseases, X-Linked, medicine, Humans, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neonatology, MESH: Prenatal Diagnosis, MESH: Arylsulfatases, MESH: Maxillofacial Development, 030304 developmental biology, MESH: Mutation, Missense, MESH: Humans, business.industry, Epiphyseal stippling, MESH: Pregnancy Outcome, medicine.disease, MESH: Chondrodysplasia Punctata, Osteochondrodysplasia, MESH: Male, Face, Pediatrics, Perinatology and Child Health, business, MESH: Female
Abstract

International audience; We report the prenatal management of a brachytelephalangic chondrodysplasia punctata (CDPX1) case and how postnatal findings confirmed the diagnosis. The mother was initially referred after ultrasound revealed an abnormal fetal mid-face and punctuation of upper femoral epiphyses. Chondrodysplasia punctata (CP) with Binder anomaly was suspected. 3D-HCT revealed brachytelephalangy suggesting CDPX1. At birth, mid-face hypoplasia was marked. Postnatal imaging and genetic analysis confirmed the initial diagnosis. Binder anomaly is probably always associated with CP. The newly revised CP classification facilitates the diagnosis. The main etiologies are metabolic and chromosomal abnormalities, and arylsulfatase E enzyme dysfunction. Thus, screening for arylsulfatase E mutation is mandatory for an accurate diagnosis and can lead to better delineation among CP etiologies associated with a Binder phenotype.

Published
2010
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35. Surface characterizations of fluorescent-functionalized silica nanoparticles: from the macroscale to the nanoscale

Author

Wai Li Ling, Olivier Poncelet, Olivier Raccurt, Peter Cherns, Didier Grunwald, Olivier Tillement, Jorice Samuel, Aurélien Auger, Département des Technologies des NanoMatériaux ( DTNM ), Laboratoire d'Innovation pour les Technologies des Energies Nouvelles et les nanomatériaux ( LITEN ), Institut National de L'Energie Solaire ( INES ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre Scientifique et Technique du Bâtiment ( CSTB ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre Scientifique et Technique du Bâtiment ( CSTB ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de L'Energie Solaire ( INES ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre Scientifique et Technique du Bâtiment ( CSTB ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre Scientifique et Technique du Bâtiment ( CSTB ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Laboratoire d'Electronique et des Technologies de l'Information ( CEA-LETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes [Saint Martin d'Hères], ANTE-INSERM U836, équipe 4, Muscles et pathologies, Transduction du signal : signalisation calcium, phosphorylation et inflammation, Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Physico-Chimie des Matériaux Luminescents ( LPCML ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Département des Technologies des NanoMatériaux (DTNM), Laboratoire d'Innovation pour les Technologies des Energies Nouvelles et les nanomatériaux (LITEN), Institut National de L'Energie Solaire (INES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Institut National de L'Energie Solaire (INES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physico-Chimie des Matériaux Luminescents (LPCML), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Roux-Buisson, Nathalie, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Materials science, Characterization, Nanoparticle, Bioengineering, Nanotechnology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Nano, Zeta potential, General Materials Science, Thin film, Functionalization, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Nanoscopic scale, chemistry.chemical_classification, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Silica, General Chemistry, Polymer, Dispersion, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Fluorescence, Atomic and Molecular Physics, and Optics, 0104 chemical sciences, chemistry, Coupling agent, Modeling and Simulation, Nanoparticles, Surface modification, 0210 nano-technology
Abstract

International audience; Fluorescent silica nanoparticles are widely used for various applications from mechanical reinforcement to biology. In many cases, their surface has to be tailored. Herein fluorescent silica nanoparticles are synthesized by a reverse micro-emulsion process and functionalized by silane coupling agents owning amino and thiol groups. The functionalization is then characterized by macroscopic well-known methods (zeta potential, hydrophilic to hydrophobic ratio, etc.) and an original method based onto TEM observations of the contrast between the silica core and the metallic ions chelated by the functional groups grafted onto the surface is also introduced. This method reveals that the functionalization is effective and that it occurs by ''nano domains.'' It is therefore possible to characterize the functionalization by in situ observations. Finally, the characterized nanoparticles are incorporated into a PMMA thin film. The fluorescence of the nanoparticles allows the monitoring of the level of dispersion of the nanoparticles within the polymer and confirms all the other characterizations.

Published
2009
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36. Mutations inTPM3are a common cause of congenital fiber type disproportion

Author

Michael C Fahey, Norma B. Romero, Robert L. Smith, Annick Labarre-Vila, Rakesh Patel, Nigel F. Clarke, Danielle E. Dye, Edward S. Johnson, Nicole Monnier, Hannah Kolski, Remi Bellance, Kathryn N. North, Nigel G. Laing, Esther Lim, Institute for Neuromuscular Research, The University of Sydney, Division of Pediatric Neurology, University of Alberta, Centre for Medical Research, The University of Western Australia (UWA), John Hunter Children's Hospital, University Discipline of Paediatrics and Child Health, Starship Children's Hospital, University of Auckland [Auckland], Monash Neurology, Monash Medical Centre [Clayton, Australia], Centre de Référence Maladies Rares Neurologiques et Neuromusculaires, CHU Fort de France, 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), Department of Laboratory Medicine and Pathology, Centre de Référence des Maladies Neuromusculaires, CHU Grenoble, Laboratoire de biochimie et génétique moléculaire, and Roux-Buisson, Nathalie

Subjects
Male, Pathology, MESH: Tropomyosin, Tropomyosin, TPM2, Cohort Studies, MESH: Genetic Screening, 0302 clinical medicine, Nemaline myopathy, Ptosis, MESH: Child, Missense mutation, Child, MESH: Cohort Studies, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Facial weakness, Middle Aged, Congenital fiber type disproportion, Pedigree, 3. Good health, Neurology, Child, Preschool, Female, medicine.symptom, Myopathies, Structural, Congenital, Adult, medicine.medical_specialty, Adolescent, MESH: Myopathies, Structural, Congenital, MESH: Pedigree, Mutation, Missense, Tropomyosin 3, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Testing, education, 030304 developmental biology, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, Congenital myopathy, MESH: Male, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE: Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding alpha-tropomyosin(slow) (TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD. METHODS AND RESULTS: We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant. INTERPRETATION: Mutation of TPM3 is the most common cause of CFTD reported to date.

Published
2008
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37. Functional characterization of a Central Core Disease RyR1 mutation (p.Y4864H) associated with quantitative defect in RyR1 protein

Author

Vincent Mouly, Isabelle Marty, Julien Fauré, Renée Krivosic, Nathalie Roux-Buisson, Joël Lunardi, Arnaud Lacour, Julie Brocard, Nicole Monnier, Paul D. Allen, Anne-Sophie Wozny, Marine Cacheux, Muriel Sébastien, Kamel Mamchaoui, John Rendu, Ariane Blum, 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), 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), Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Département Anesthésie-Réanimation, Hôpital Roger Salengro, CHRU de Lille, Hôpital Roger Salengro, CHRU de Lille, Lille, France, Department of Molecular Biosciences, Department of Molecular Biosciences [Oslo], Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Roux-Buisson, Nathalie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), and Service de Neurologie, Hôpital Roger Salengro

Subjects
Research Report, medicine.medical_specialty, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Biology, Calcium, medicine.disease_cause, Malignant hyperthermia, Calcium imaging, Central Core Disease, Internal medicine, medicine, RYR1, Mutation, Ryanodine receptor, Calcium channel, Muscle weakness, medicine.disease, musculoskeletal system, [SDV] Life Sciences [q-bio], Endocrinology, Neurology, Biochemistry, chemistry, Neurology (clinical), medicine.symptom, tissues, calcium release
Abstract

International audience; BACKGROUND: Central Core Disease (CCD) is a congenital myopathy often resulting from a mutation in RYR1 gene. Mutations in RyR1 can increase or decrease channel activity, or induce a reduction in the amount of protein. The consequences of a single mutation are sometimes multiple and the analysis of the functional effects is complex.OBJECTIVE: The consequences of the p.Y4864H mutation identified in a CCD patient have been studied regarding both RyR1 function and amount.METHODS: The amount of RyR1 in human and mouse muscles was evaluated using qRT-PCR and quantitative Western blot, and calcium release was studied using calcium imaging on primary cultures. The results were compared between human and mouse.RESULTS: The p.Y4864H mutation induced an alteration of calcium release, and in addition was associated to a reduction in the amount of RyR1 in the patient’s muscle. This suggests two possible pathophysiological mechanisms: the alteration of calcium release could result from a modification of the channel properties of RyR1 or from a RyR1 reduction. In order to discriminate between the two hypotheses, we used the heterozygous RyR1 knockout (RyR1+/-) mouse model showing a comparable RyR1 protein reduction. No reduction in calcium release was observed in primary muscle culture from these mice, and no muscle weakness was measured.CONCLUSIONS: Because the reduction in the amount of RyR1 protein has no functional consequences in the murine model, the muscle weakness observed in the patient is most likely the result of a modification of the calcium channel function of RyR1 due to the p.Y4864H mutation.

Published
2015
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38. Muscle imaging in dominant core myopathies linked or unlinked to the ryanodine receptor 1 gene

Author

Michel Fardeau, Héctor Manuel Barragán-Campos, Nicole Monnier, Norma B. Romero, Svetlana Maugenre, Joël Lunardi, Jean-Paul Leroy, Dirk Fischer, Ana Ferreiro, Jacques Chiras, Muriel Herasse, Pascale Guicheney, Louis Viollet, 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), Muskellabor, Rheinische Friedrich-Wilhelms-Universität Bonn, Muskelzentrum/ALS Clinic, Kantonsspital St. Gallen, Institut de Myologie, 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), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service d'anatomie pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), DFG, BONFOR, Association Française contre les Myopathies, PHRC., Collaboration, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Roux-Buisson, Nathalie

Subjects
medicine.medical_specialty, Statistics as Topic, MESH: Myopathy, Central Core, Chromosome Disorders, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Gene mutation, MESH: Ryanodine Receptor Calcium Release Channel, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Myopathy, Central Core, Muscle, Skeletal, Myopathy, MESH: Statistics as Topic, RYR1, MESH: Chromosome Disorders, MESH: Muscle, Skeletal, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, MESH: Humans, biology, Genetic heterogeneity, Ryanodine receptor, Gluteus minimus, 030305 genetics & heredity, MESH: Genetic Predisposition to Disease, Ryanodine Receptor Calcium Release Channel, musculoskeletal system, medicine.disease, biology.organism_classification, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MYH7, Neurology (clinical), medicine.symptom, tissues, 030217 neurology & neurosurgery, Central core disease
Abstract

Objective: To characterize the muscle involvement of patients with central core disease (CCD) caused by mutations in the ryanodine receptor 1 gene ( RYR1 ) and to compare these findings with those from patients with core myopathies unlinked to the RYR1 gene. Methods: We performed a systematic muscular imaging assessment in 11 patients with an RYR1 gene mutation and compared these findings with those of 5 patients from two unrelated families with autosomal dominant core myopathies not linked to RYR1 , ACTA1 , or MYH7 gene loci. Results: All patients with RYR1 CCD had a characteristic pattern with predominant involvement of the gluteus maximus, adductor magnus, sartorius, vastus intermediolateralis, soleus, and lateral gastrocnemius muscles. In contrast, muscle CT in the first family not linked to RYR1 showed predominant affection of the gluteus minimus and hamstring muscles, whereas the second family presented with predominant involvement of the gluteus minimus, vastus intermediolateralis, tibialis anterior, and medial gastrocnemius muscles. In addition to muscle imaging data, we present detailed information on the clinical and pathologic findings of these novel phenotypes of core myopathies not linked to RYR1 . Conclusions: Our data suggest genetic heterogeneity in autosomal dominant core myopathies and the existence of additional unidentified genes.

Published
2006
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39. Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes

Author

Clemens R. Müller, Susan Treves, Francesco Muntoni, Ana Ferreiro, Francesco Zorzato, Nicole Monnier, Heinz Jungbluth, Sylvie Ducreux, Department of Anaesthesia and Research, University Hospital Basel [Basel], Dipartimento di Medicina Sperimentale e Diagnostica, Università degli Studi di Ferrara (UniFE), 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 Dubowitz Neuromuscular Centre, Imperial College London, Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut für Humangenetik, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Swiss National Science Foundation, Department of Anaesthesia, Basel University Hospital, Association Française contre les Myopathies, Muscular Dystrophy Campaign, German MD-Net Bundesministerium für Bildung und Forschung., Università degli Studi di Ferrara = University of Ferrara (UniFE), Julius-Maximilians-Universität Würzburg (JMU), and Roux-Buisson, Nathalie

Subjects
Herpesvirus 4, Human, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Thapsigargin, Biochemistry, MESH: Caffeine, MESH: Ryanodine Receptor Calcium Release Channel, MESH: Dose-Response Relationship, Drug, Calcium channel, Central core disease, Lymphoblastoid cell line, Malignant hyperthermia, Multi-minicore disease, Ryanodine receptor, Cresols, 0302 clinical medicine, Lymphocytes, Myopathy, Central Core, MESH: DNA Mutational Analysis, Receptor, Cells, Cultured, chemistry.chemical_classification, 0303 health sciences, MESH: Drug Screening Assays, Antitumor, MESH: Amino Acid Substitution, MESH: Case-Control Studies, 3. Good health, Amino acid, MESH: Cresols, medicine.anatomical_structure, Thapsigargin, Intracellular, MESH: Cells, Cultured, Research Article, medicine.medical_specialty, MESH: Mutation, MESH: Myopathy, Central Core, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Calcium Signaling, 03 medical and health sciences, Caffeine, Internal medicine, medicine, Humans, Calcium Signaling, Molecular Biology, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Dose-Response Relationship, Drug, Skeletal muscle, MESH: Herpesvirus 4, Human, Ryanodine Receptor Calcium Release Channel, Cell Biology, medicine.disease, Molecular biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, chemistry, Case-Control Studies, Mutation, MESH: Lymphocytes, Drug Screening Assays, Antitumor, 030217 neurology & neurosurgery, Homeostasis
Abstract

International audience; More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and central core disease, and with recessive forms of multi-minicore disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (central core disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-minicore disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein-Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.

Published
2006
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40. Ryanodine receptor 1 and associated pathologies

Author

Joël Lunardi, Isabelle Marty, Julien Fauré, Nicole Monnier, Roux-Buisson, Nathalie, Weiss, N. Koschak, A., 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)-Service Biochimie et Génétique Moléculaire, CHU Grenoble-CHU Grenoble, 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), Weiss, N. Koschak, and A.

Subjects
RYR1, 0303 health sciences, Ryanodine receptor, Malignant hyperthermia, chemistry.chemical_element, Skeletal muscle, Calcium, medicine.disease, musculoskeletal system, Sarcomere, Calcium in biology, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, chemistry, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Myopathy, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

In skeletal muscle a rise in the cytosolic calcium concentration is the first trigger able to initiate the contraction of the sarcomere. Intracellular calcium levels are tightly controlled by channels and pumps, and it is not surprising that many inherited skeletal muscle disorders arise from mutations altering the players regulating calcium ions concentration (Betzenhauser and Marks 2010). In this chapter, we will focus on the pathologies linked to the sarcoplasmic reticulum calcium channel-RyR1 mutations.

Published
2014
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41. 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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42. Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3

Author

Andrew J. Kornberg, Nigel F. Clarke, Paul Kennedy, Leigh B. Waddell, Nicole Monnier, Michaela Kreissl, Kathryn N. North, Annick Labarre-Vila, Catriona McLean, Institute for Neuroscience and Muscle Research, Westmead Hospital [Sydney], Discipline of Paediatrics and Child Health, The University of Sydney, Department of Neurology, Royal Children's Hospital, State Neuropathology Service, Department of Pathology, University of Melbourne, Department of Anatomical Pathology, The Alfred Hospital, Centre de Reference des Maladies Neuromusculaires, CHU Grenoble, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biochimie et génétique moléculaire, This work has been supported by the NHMRC, Australia (N.C. - Grant 206529 and 571287, L.W. - Grant 505004 and K.N. - Grant 403941) and the MDA of New South Wales (N.C., K.N.)., and Roux-Buisson, Nathalie

Subjects
Male, Pathology, medicine.medical_specialty, MESH: Mutation, Adolescent, Dominant negative, MESH: Tropomyosin, Tropomyosin, Disease, Biology, Arginine, Sarcomere, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Cap myopathy, Mutant protein, Dominant negative disease, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cysteine, Muscle, Skeletal, Genetics (clinical), 030304 developmental biology, MESH: Adolescent, MESH: Muscle, Skeletal, 0303 health sciences, MESH: Humans, Mechanism (biology), MESH: Child, Preschool, MESH: Arginine, MESH: Muscular Diseases, MESH: Cysteine, MESH: Male, 3. Good health, Congenital fibre-type disproportion, TPM3, Neurology, Child, Preschool, Causal association, Mutation, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery
Abstract

International audience; We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.

Published
2010
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43. 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
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44. An ABC transporter and an outer membrane lipoprotein participate in posttranslational activation of type VI secretion in Pseudomonas aeruginosa

Author

Casabona, Maria, Silverman, Julie, Sall, Khady, Boyer, Frédéric, Couté, Yohann, Poirel, Jessica, Grunwald, Didier, Mougous, Joseph, Elsen, Sylvie, Attree, Ina, Pathogénie bactérienne et réponses cellulaires, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Microbiology, University of Washington [Seattle], Laboratoire d'Ecologie Alpine (LECA), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaincre la mucoviscidose/NIH, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), 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 Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), ANTE-INSERM U836, équipe 4, Muscles et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Biologie du Cancer et de l'Infection (BCI ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-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 Grenoble Alpes (UGA)-Pathogénie bactérienne et réponses cellulaires, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-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)-Université Grenoble Alpes (UGA)-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)-Pathogénie bactérienne et réponses cellulaires, Roux-Buisson, Nathalie, and Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)

Subjects
Molecular Sequence Data, Biological Transport, Gene Expression Regulation, Bacterial, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, Phosphoric Monoester Hydrolases, Article, Pseudomonas aeruginosa, ATP-Binding Cassette Transporters, Amino Acid Sequence, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Bacterial Secretion Systems, Sequence Alignment, Gene Deletion, Bacterial Outer Membrane Proteins, Genome-Wide Association Study, Signal Transduction
Abstract

International audience; Pseudomonas aeruginosa is capable of injecting protein toxins into other bacterial cells through one of its three type VI secretion systems (T6SSs). The activity of this T6SS is tightly regulated on the posttranslational level by phosphorylation-dependent and -independent pathways. The phosphorylation-dependent pathway consists of a Threonine kinase/phosphatase pair (PpkA/PppA) that acts on a forkhead domain-containing protein, Fha1, and a periplasmic protein, TagR, that positively regulates PpkA. In the present work, we biochemically and functionally characterize three additional proteins of the phosphorylation-dependent regulatory cascade that controls T6S activation: TagT, TagS and TagQ. We show that similar to TagR, these proteins act upstream of the PpkA/PppA checkpoint and influence phosphorylation of Fha1 and, apparatus assembly and effector export. Localization studies demonstrate that TagQ is an outer membrane lipoprotein and TagR is associated with the outer membrane. Consistent with their homology to lipoprotein outer membrane localization (Lol) components, TagT and TagS form a stable inner membrane complex with ATPase activity. However, we find that outer membrane association of T6SS lipoproteins TagQ and TssJ1, and TagR, is unaltered in a ΔtagTS background. Notably, we found that TagQ is indispensible for anchoring of TagR to the outer membrane fraction. As T6S-dependent fitness of P. aeruginosa requires TagT, S, R and Q, we conclude that these proteins likely participate in a trans-membrane signalling pathway that promotes H1-T6SS activity under optimal environmental conditions.

Published
2013
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45. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis

Author

André Mégarbané, Cécile Laroche, Isabelle Marty, Klaus Dieterich, Nicole Monnier, Damien Sternberg, Pierre-Simon Jouk, Jie Zhou, Susana Quijano-Roy, Daniela Avila Smirnow, Pascale Marcorelles, Robert Carlier, Sylvie Odent, Brigitte Estournet, Julien Fauré, Norma B. Romero, Sandra Mercier, Judith Melki, Joël Lunardi, INSERM U836, équipe 4, Muscles et pathologies, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-IFR93-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Génétique et Procréation, CHU Grenoble-CHU Grenoble-Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant-Hôpital Couple Enfant, Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie Génétique et Moléculaire, CHU Grenoble-Institut de Biologie et de Pathologie (IBP)-CHU Grenoble-Institut de Biologie et de Pathologie (IBP), Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant, Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Anatomopathologie, Institut de Myologie, 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)-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique et Procréation, CHU Grenoble, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Pyopathies, PHRC (AOM 10181), Inserm, 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 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)-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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Roux-Buisson, Nathalie

Subjects
Central Nervous System, Pathology, Genetic Linkage, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Compound heterozygosity, Endothelins, Consanguinity, Mice, 0302 clinical medicine, MESH: Embryonic Development, MESH: Animals, 10. No inequality, Genetics (clinical), Arthrogryposis, Motor Neurons, 0303 health sciences, Mutation, Homozygote, Chromosome Mapping, Metalloendopeptidases, General Medicine, Anatomy, Muscle atrophy, 3. Good health, Pedigree, Phenotype, medicine.symptom, MESH: Motor Neurons, MESH: Homozygote, medicine.hormone, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, MESH: Arthrogryposis, MESH: Genetic Linkage, MESH: Metalloendopeptidases, Embryonic Development, Genes, Recessive, Biology, MESH: Phenotype, 03 medical and health sciences, Genetics, medicine, MESH: Central Nervous System, Animals, Humans, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Muscle contracture, MESH: Consanguinity, [SDV.GEN]Life Sciences [q-bio]/Genetics, Arthrogryposis multiplex congenita, MESH: Humans, Heterozygote advantage, MESH: Chromosome Mapping, 030217 neurology & neurosurgery
Abstract

International audience; Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes. Using a pangenomic approach, we demonstrated linkage of DA to chromosome 2q37 in two consanguineous families and the endothelin-converting enzyme like 1 (ECEL1) gene present in this region was associated with DA. Screening of a panel of 20 families with non-specific DA identified seven homozygous or compound heterozygous mutations of ECEL1 in a total of six families. Mutations resulted mostly in the absence of protein. ECEL1 is a neuronal endopeptidase predominantly expressed in the central nervous system and brain structures during fetal life in mice and human. ECEL1 plays a major role in intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis. A detailed review of clinical findings of DA patients with ECEL1 mutations revealed a homogeneous and recognizable phenotype characterized by limited knee flexion, flexed third to fifth fingers and severe muscle atrophy predominant on lower limbs and tongue that suggested a common pathogenic mechanism. We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction.

Published
2012
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46. An integrated diagnosis strategy for congenital myopathies

Author

Julie Brocard, Isabelle Marty, Nicole Monnier, Marion Gérard, Edoardo Malfatti, Christine Kretz, Maggie C. Walter, Norma B. Romero, Bernard Jost, H. Karasoy, Valérie Biancalana, Nadia Messaddeq, Joël Lunardi, Stéphanie Le Gras, Jocelyn Laporte, Claire Feger, Nasim Vasli, Peter Reilich, Johann Böhm, Ege Üniversitesi, 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), Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Neurological, Neurosurgical, and Behavioral Sciences, 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), DNA Microarrays and Sequencing Platform, ANTE-INSERM U836, équipe 4, Muscles et pathologies, Biochimie Génétique et Moléculaire, CHU Grenoble-CHU Grenoble, 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), Department of Neurology, Ege University School of Medicine, Service de Génétique [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), Ludwig-Maximilians-Universität München (LMU)-Friedrich-Baur-Institute, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Imaging Center, CHU Grenoble, This work was supported by Institut National de la Sante' et de la Recherche Me'dicale (INSERM), Centre national de la recherche scientifique (CNRS), University of Strasbourg, Colle'ge de France and grants from ANR, GIS Institute for rare diseases and IBiSA, Association Francaise contre les myopathies, Muscular Dystrophy Association (United States of America) and the Myotubular Trust. This work was supported by the INSERM, the CNRS, University of Strasbourg, Colle'ge de France and grants from the Agence Nationale de la Recherche (ANR, grant CM-WES), Muscular Dystrophy Association (MDA, grant 2010-52655) and Myotubular Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Collège de France - Chaire Génétique Humaine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), and Roux-Buisson, Nathalie

Subjects
Male, Pathology, Genetic Screens, Heredity, Biopsy, DNA Mutational Analysis, Gene Identification and Analysis, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, 0302 clinical medicine, Missense mutation, Exome, lcsh:Science, Exome sequencing, 0303 health sciences, Multidisciplinary, Muscles, Linkage (Genetics), 3. Good health, Pedigree, Phenotype, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Research Article, Adult, medicine.medical_specialty, Histology, Nonsense mutation, Molecular Sequence Data, Genetic Counseling, Biology, Muscle disorder, Molecular Genetics, 03 medical and health sciences, Nebulin, Muscular Diseases, Genetic Mutation, medicine, Genetics, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetic Testing, Myopathy, 030304 developmental biology, Congenital Hereditary Myopathies, RYR1, Clinical Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genetic heterogeneity, lcsh:R, Human Genetics, Sequence Analysis, DNA, Mutation, Genetics of Disease, biology.protein, lcsh:Q, 030217 neurology & neurosurgery
Abstract

WOS: 000321738400157, PubMed ID: 23826317, Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity., Institut National de la Sante et de la Recherche Medicale (INSERM)Institut National de la Sante et de la Recherche Medicale (Inserm); Centre national de la recherche scientifique (CNRS)Centre National de la Recherche Scientifique (CNRS); University of Strasbourg; College de France; GIS Institute; Association Francaise contre les myopathiesAssociation Francaise contre les Myopathies; Muscular Dystrophy Association (United States of America)Muscular Dystrophy Association; Myotubular Trust; Agence Nationale de la Recherche (ANR)French National Research Agency (ANR); Muscular Dystrophy Association (MDA)Muscular Dystrophy Association [2010-52655], This work was supported by Institut National de la Sante et de la Recherche Medicale (INSERM), Centre national de la recherche scientifique (CNRS), University of Strasbourg, College de France and grants from ANR, GIS Institute for rare diseases and IBiSA, Association Francaise contre les myopathies, Muscular Dystrophy Association (United States of America) and the Myotubular Trust. This work was supported by the INSERM, the CNRS, University of Strasbourg, College de France and grants from the Agence Nationale de la Recherche (ANR, grant CM-WES), Muscular Dystrophy Association (MDA, grant 2010-52655) and Myotubular Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2012
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47. 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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48. 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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49. Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy

Author

James J. Dowling, S. Arbogast, John Y. Kuwada, Isabelle Marty, Susan V. Brooks, Joël Lunardi, Darcee D. Nelson, Ana Ferreiro, Junguk Hur, A. McEvoy, Trent Waugh, Roux-Buisson, Nathalie, Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Neurology, Groupe Myologie, Institut de Myologie, 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)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biomedical Engineering, 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), 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, Department of Molecular and Integrated Physiology, Department Molecular, Cellular, and Developmental Biology, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), National Institutes of Health (1K08AR054835 to J.J.D., R01NS54731 to J.Y.K. and AG-020591 to S.V.B.), the Child Neurology Foundation (J.J.D.) and the National Science Foundation (NSF 0725976 to J.Y.K.). Additional support was from Endostem (FP7 grant to S.A.), the ANR (Agence Nationale pour la Recherche, MyCa grant), the INSERM (Institut National de la Santé et la Recherche Mé dicale) and the AP-HP (Assistance Publique-Hôpitaux de Paris, Contrat d'Interface to A.F.)., and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
MESH: Muscle Contraction, Indomethacin, Muscle Fibers, Skeletal, Muscle Proteins, Mitochondrion, neuromuscular disorders, medicine.disease_cause, Antioxidants, MESH: Ryanodine Receptor Calcium Release Channel, Animals, Genetically Modified, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Enzyme Inhibitors, Zebrafish, 0303 health sciences, MESH: Indomethacin, MESH: Muscle Fibers, Skeletal, MESH: Oxidative Stress, biology, Behavior, Animal, Myogenesis, 3. Good health, Cell biology, Mitochondria, MESH: Enzyme Inhibitors, Larva, myopathies, MESH: Microscopy, Electron, Transmission, medicine.symptom, Muscle Contraction, medicine.medical_specialty, MESH: Mutation, antioxidant response, MESH: Mitochondria, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Acetylcysteine, Microscopy, Electron, Transmission, Muscular Diseases, In vivo, Internal medicine, medicine, Animals, Humans, Myopathy, MESH: Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, RYR1, MESH: Humans, MESH: Antioxidants, MESH: Muscular Diseases, Acetophenones, Ryanodine Receptor Calcium Release Channel, Original Articles, biology.organism_classification, Microarray Analysis, Acetylcysteine, MESH: Microarray Analysis, Disease Models, Animal, Oxidative Stress, Endocrinology, MESH: Acetophenones, Mutation, Neurology (clinical), MESH: Disease Models, Animal, MESH: Larva, 030217 neurology & neurosurgery, Ex vivo, Oxidative stress
Abstract

International audience; The skeletal muscle ryanodine receptor is an essential component of the excitation-contraction coupling apparatus. Mutations in RYR1 are associated with several congenital myopathies (termed RYR1-related myopathies) that are the most common non-dystrophic muscle diseases of childhood. Currently, no treatments exist for these disorders. Although the primary pathogenic abnormality involves defective excitation-contraction coupling, other abnormalities likely play a role in disease pathogenesis. In an effort to discover novel pathogenic mechanisms, we analysed two complementary models of RYR1-related myopathies, the relatively relaxed zebrafish and cultured myotubes from patients with RYR1-related myopathies. Expression array analysis in the zebrafish disclosed significant abnormalities in pathways associated with cellular stress. Subsequent studies focused on oxidative stress in relatively relaxed zebrafish and RYR1-related myopathy myotubes and demonstrated increased oxidant activity, the presence of oxidative stress markers, excessive production of oxidants by mitochondria and diminished survival under oxidant conditions. Exposure to the antioxidant N-acetylcysteine reduced oxidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo and led to significant restoration of aspects of muscle function in the relatively relaxed zebrafish, thereby confirming its efficacy in vivo. We conclude that oxidative stress is an important pathophysiological mechanism in RYR1-related myopathies and that N-acetylcysteine is a successful treatment modality ex vivo and in a vertebrate disease model. We propose that N-acetylcysteine represents the first potential therapeutic strategy for these debilitating muscle diseases.

Published
2012
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50. Unique biofilm signature, drug susceptibility and decreased virulence in Drosophila through the Pseudomonas aeruginosa two-component system PprAB

Author

Friederike Ewald, Cathy Nguyen, Marie-Odile Fauvarque, Ina Attree, Virginie Calderon, Katy Jeannot, Sophie de Bentzmann, Christophe Bordi, Christophe S. Bernard, Didier Grunwald, Patrick Plésiat, Caroline Giraud, Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de microbiologie et génétique moléculaires (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de bactériologie, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANTE-INSERM U836, équipe 4, Muscles et pathologies, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), French cystic fibrosis foundation, French Ministry of Research and Technology, Region Rhône-Alpes, European Project, Roux-Buisson, Nathalie, ERA-NET ADHRES 27481, INCOMING, Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénie bactérienne et réponses cellulaires, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches en Technologies et Sciences pour le Vivant (IRTSV), 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 Grenoble Alpes (UGA), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and 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)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
MESH: Adhesins, Bacterial, Fimbria, Pathogenesis, medicine.disease_cause, MESH: Animals, Biology (General), MESH: Bacterial Secretion Systems, Bacterial Secretion Systems, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Genomics, 3. Good health, Bacterial Pathogens, Host-Pathogen Interaction, Drosophila melanogaster, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, Research Article, QH301-705.5, Immunology, Virulence, MESH: Biofilms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microbiology, Bacterial genetics, Cell Line, MESH: Drosophila melanogaster, MESH: Fimbriae, Bacterial, 03 medical and health sciences, Virology, medicine, Genetics, Animals, Secretion, Adhesins, Bacterial, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, 030306 microbiology, fungi, Biofilm, Bacteriology, RC581-607, MESH: Cell Line, Bacterial adhesin, Regulon, Biofilms, Fimbriae, Bacterial, Parasitology, Immunologic diseases. Allergy
Abstract

Bacterial biofilm is considered as a particular lifestyle helping cells to survive hostile environments triggered by a variety of signals sensed and integrated through adequate regulatory pathways. Pseudomonas aeruginosa, a Gram-negative bacterium causing severe infections in humans, forms biofilms and is a fantastic example for fine-tuning of the transition between planktonic and community lifestyles through two-component systems (TCS). Here we decipher the regulon of the P. aeruginosa response regulator PprB of the TCS PprAB. We identified genes under the control of this TCS and once this pathway is activated, analyzed and dissected at the molecular level the PprB-dependent phenotypes in various models. The TCS PprAB triggers a hyper-biofilm phenotype with a unique adhesive signature made of BapA adhesin, a Type 1 secretion system (T1SS) substrate, CupE CU fimbriae, Flp Type IVb pili and eDNA without EPS involvement. This unique signature is associated with drug hyper-susceptibility, decreased virulence in acutely infected flies and cytotoxicity toward various cell types linked to decreased Type III secretion (T3SS). Moreover, once the PprB pathway is activated, decreased virulence in orally infected flies associated with enhanced biofilm formation and dissemination defect from the intestinal lumen toward the hemolymph compartment is reported. PprB may thus represent a key bacterial adaptation checkpoint of multicellular and aggregative behavior triggering the production of a unique matrix associated with peculiar antibiotic susceptibility and attenuated virulence, a particular interesting breach for therapeutic intervention to consider in view of possible eradication of P. aeruginosa biofilm-associated infections., Author Summary We unraveled that once the two-component system PprAB regulatory pathway is activated, Pseudomonas aeruginosa displays a unique hyper-biofilm phenotype due to a molecular signature combining a T1SS high molecular weight substrate, BapA, fimbriae of the chaperone-usher pathway, Type IVb pili and eDNA. Originally, this particular hyper-biofilm that is not strictly dependent on Psl or Pel exopolysaccharide (EPS) synthesis displays increased drug susceptibility, in contrary to previously reported biofilm lifestyle associated with increased resistance to antibiotics. PprB-dependent hyper-biofilm was also observed on intestinal mucosa of orally infected Drosophila flies in which it also displays a reduced capacity to cross the epithelial barrier from the intestinal lumen toward the hemolymph that consequently resulted in a reduced capacity to kill flies. Furthermore, constitutive activation of this PprB regulatory pathway triggers a reduced secretion of T3SS effectors which may account for the decreased virulence observed in epithelial and macrophage lineages and in acute Drosophila infections induced by septic injury. We appended in this study pieces of regulatory and molecular data that highlight the possibility to combat infections due to P. aeruginosa-biofilm with particular matrix.

Published
2012
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