Author: "Nicole Monnier" - Searchworks@Jio Institute Digital Library Search Results

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1. An integrated diagnosis strategy for congenital myopathies.

Author: Johann Böhm, Nasim Vasli, Edoardo Malfatti, Stéphanie Le Gras, Claire Feger, Bernard Jost, Nicole Monnier, Julie Brocard, Hatice Karasoy, Marion Gérard, Maggie C Walter, Peter Reilich, Valérie Biancalana, Christine Kretz, Nadia Messaddeq, Isabelle Marty, Joël Lunardi, Norma B Romero, and Jocelyn Laporte
Subjects: Medicine, Science
Abstract: 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.
Published: 2013
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2. Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

Author: Cécile Couchoud, Florian Bayer, Carole Ayav, Clémence Béchade, Philippe Brunet, François Chantrel, Luc Frimat, Roula Galland, Maryvonne Hourmant, Emmanuelle Laurain, Thierry Lobbedez, Lucile Mercadal, Olivier Moranne, Abdelhamid Abbassi, Alain Debure, Abdallah Guerraoui, Abdelatif Benmoussa, Abdelaziz Hamani, Abdelaziz Ziane, Abdelhamid Nefti, Abdelkader Hadj, Abderrahim El Amari, Abderrahmane Ghazali, Abo Bakr Abd El Fatah Mohamed, Achour Laradi, Adel Ben Ahmed, Adel Sahar, Adele Pillet, Adeline Lacraz, Adnan Moinat, Afshin Massoumi, Agathe Pardon, Agnes Caillette Beaudoin, Agnes Chapelet Debout, Agnes Mariot, Ahmed Rachi, Aida Afiani, Aime Remy Boula, Al Jalaby, Alain Cremault, Alain Fournier, Alain Jeanson, Alain Lyon, Alain Nony, Alain Robert, Alain Slingeneyer, Alanor Agnes Labatide, Albane Brodin Sartorius, Albert Bensman, Albert Fournier, Alex Ranlin, Alex Vido Sandor, Alexandra Colombo, Alexandra Duhem, Alexandra Stancu, Alexandre Dufay, Alexandre Dumoulin, Alexandre Ebel, Alexandre Klein, Alexandre Martin, Alexandre Mouneimne, Alexandre Seidowsky, Alfio De Martin, Alfredo Zannier, Ali Aizel, Ali Hafi, Ali Zineddine Diddaoui, Alim Heyani, Alina Mocanu, Alina Preda, Aline Hafi, Aline Talaszka, Alyette Duquesne, Amar Amaouche, Amel Ghemmour, Amelie Simon, Amina Skalli, Amine Boukadida, Amr Ekhlas Ragab Eid, Ana Fedorca, Anabelle Baillet, Anais Poyet, Ancuta Bouffandeau Giorgita, Anderson Ratsimbazafy, Andre Pruna, Angel Argiles, Angelo Testa, Ann Karolien Vandooren, Anne Jolivot, Anne Kolko Labadens, Anne Lataste, Anne Maisin, Anne Paris, Anne Sechet, Anne Wuillai, Anne Elisabeth Heng, Anne Gaelle Josse, Anne Helene Querard, Anne Helene Reboux, Anne Laure Adra, Anne Laure Faller, Anne Laure Leclerc, Anne Laure Poitou, Annie Lahoche Manucci, Antoine Jacquet, Antoine Pommereau, Antoine Thierry, Arezki Adem, Arielle Chapelet, Arnaud Del Bello, Arnaud Delezire, Arnaud Garnier, Arnaud Guerard, Arnaud Klisnick, Arnaud Lionet, Arnaud Roccabianca, Arnaud Stolz, Arthur Capdeville, Asma Allal, Assem Alrifai, Assetou Diarrassouba, Assia Djema, Assia Ferhat Carre, Astrid Godron Dubrasquet, Atman Haddj Elmrabet, Audrey Jegado, Aurelia Bertholet Thomas, Aurelie Davourie Salandre, Aurelie Pajot, Aurelien Lorthioir, Aurelien Tiple, Aurore Sury, Ayman Abokasem, Ayman Sarraj, Bachir Henaoui, Baher Chaghouri, Bassem Wehbe, Beatrice Ball, Beatrice Viron, Belkassem Issad, Benedicte Hodemon Corne, Benedicte Janbon, Benjamin Deroure, Benjamin Savenkoff, Benoit Jonon, Benoit Vendrely, Benyakoub Djelaleddine, Bernard Ohry, Bernard Painchart, Bernard Strullu, Bernard Temperville, Bertin Ebikili, Bertrand Hacq, Bertrand Morel, Bilal Aoun, Blanca Muniz, Bouchra Chlih, Brahim Amara, Brice Mayor, Brigitte Gilson, Brigitte Llanas, Brigitte Zins, Bruno Bourgeon, Bruno Coevoet, Bruno Guery, Bruno Legallicier, Bruno Paris, Bruno Ranchin, Bruno Seigneuric, Camelia Ghiciuc Dita, Camelia Prelipcean, Carine Achard Hottelart, Carine Diet, Carlos Frangie, Carlos Vela, Carmina Muresan, Carole Deprele, Caroline Araujo, Caroline Bidault, Caroline Creput, Caroline Delclaux, Caroline Du Halgouet, Caroline Favennec, Caroline Freguin, Caroline Gourraud Vercel, Caroline Mesguen, Caroline Ndomo Obama, Caroline Poitou, Caroline Preissig Dirhold, Caroline Roubiou, Catherine Albert, Catherine Bessin, Catherine De Marion Gaja, Catherine Godart, Catherine Lasseur, Catherine Leocardi, Catherine Lumbroso, Catherine Melander, Catherine Michel, Catherine Quere Maurouard, Catherine Rouannet, Catherine Taddei, Cathy Verove, Cecile Guiraud, Cecile Tafelin, Cecile Turc Baron, Cedric Formet, Cedric Pinier, Celia Lessore De Ste Foy, Celine Granolleras, Chaouki Bennini, Charles Cartou, Charles Chazot, Charlotte Jouzel, Cherif Badid, Christa Roubicek, Christel Viaud, Christelle Verrier, Christian Chuet, Christian Combe, Christian Dabot, Christian Duvic, Christian Emond, Christian Lagarde, Christian Lamotte, Christian Pain, Christiane Mousson, Christie Lorriaux, Christine Beauchamp, Christine Fumeron, Christine Le Gurun, Christine Leroy, Christine Pietrement, Christine Richer, Christophe Bouaka, Christophe Charasse, Christophe Goupy, Christophe Ridel, Cindy Castrale, Cindy Detourne, Clair Francois, Claire Presne, Claire Trivin, Clarissa Von Kotze, Claude Bernard, Claude Bonniol, Claude Desvergnes, Claude Raharivelina, Claudia Nistor, Claudine Gueret, Claudine Lloret, Claudine Saltiel, Clelia Rosati, Clementine Rabate, Corina Stanescu, Corinne Ferrandini, Corinne Guibergia, Corinne Lemoine, Corinne Passeron, Cynthia Kahil, Cyril Garrouste, Cyril Vo Van, Cyrille Jolimoy, Dalila Kesraoui, Damien Jolly, Damien Thibaudin, Dan Teboulle, Daniel Daubresse, Daniel Louvet, Daniel Rasamimanantsoa, Daniel Toledano, Daniela Babici, Daniela David, Daniela Dincu, Danielle Bruno, Delia May, Delphine Haussaire, Delphine Henriet Viprey, Denis Bugnon, Denis Fouque, Denis Morin, Derradji Nour, Diab Mohamed Mahmoud, Diana Istrati Cristescu, Didier Aguilera, Didier Coste, Didier Hamel, Didier Le Chapois, Didier Testou, Dilaver Erbilgin, Djamal Dahmane, Doan Bui Quang, Dominique Bertrand, Dominique Besnier, Dominique Blanchier, Dominique Briffa, Dominique Caux, Dominique Durand, Dominique Fleury, Dominique Guerrot, Dominique Hestin, Dominique Jaubert, Dominique Joly, Dominique Lombart, Dominique Pagniez, Dominique Pierre, Dominique Schohn, Donatien Ikonga, Dorina Visanica, Dorothee Bazin, Edouard Boury, Edouard Maksour, Ekoue Agbonon, Elarbi Harrami, Elena Marcu, Elena Tudorache, Elisabeth Caniot, Elisabeth Semjen, Elisabeth Tomkiewicz, Elise Scheidt, Elke Gaboriau, Elodie Lamouroux, Elsa Guiard, Elsa Martin Passos, Emerson Nsembani, Emilie Fache, Emilie Kalbacher, Emilie Pambrun, Emilie Pincon, Emma Allain Launay, Emmanuel Baron, Emmanuel Dupuis, Emmanuel Villar, Emmanuelle Charlin, Emmanuelle Hecquet, Emmanuelle Kohler, Emmanuelle Rosier, Enrique Figueroa, Eric Azoulay, Eric Canivet, Eric Daugas, Eric Gauthier, Eric Laruelle, Eric Le Guen, Eric Legrand, Eric Moumas, Eric Postec, Eric Prinz, Eric Renaudineau, Estelle Desport, Estelle Ricard Sutra, Etienne Berard, Etienne Ged, Etienne Robin, Eve Vilaine, Evelyne Bargas, Evelyne Mac Namara, François Combarnous, Fatima Yazbeck, Fabien Gerard, Fabien Metivier, Fabien Parazols, Fabien Soulis, Fabrice Garnier, Fadhila Pech Messaoudene, Fadi Haidar, Fanny Boullenger, Fanny Lepeytre, Fanny Leroy, Fares Frejate, Farid Bellahsene, Farid Bellhasene, Farid Saidani, Fatouma Toure, Faycal Kriaa, Fazia Nemmar, Fernando Vetromile, Florence Chalmin, Florence Lucats, Florence Sens, Florence Villemain, Florent Plasse, Fouad Lebhour, Francis Schillinger, Franck Berge, Franck Bourdon, Franck Bridoux, Franck Reynaud, Francois Babinet, Francois Basse, Francois Chantrel, Francois Clair, Francois Coulomb, Francois De Cornelissen, Francois Glowacki, Francois Marchal, Francois Maurice, Francois Nobili, Francois Pourreau, Francois Provot, Francois Roux Amani, Francoise Broux, Francoise Bulte, Francoise Heibel, Francoise Leonetti, Francoise Moussion Schott, Frank Le Roy, Frederic Besson, Frederic Lavainne, Frederic Tollis, Frederique Bocquentin, Frederique Meeus, Frederique Vecina, Friederike Von Ey, Gabriel Balit, Gabriel Choukroun, Gabriel Gruget, Gabriel Huchard, Gabriella Golea, Gabrielle Duneau, Gaelle Lefrancois, Gaelle Pelle, Gaetan Lebrun, Genevieve Dumont, Georges Brillet, Georges Deschenes, Georges Mourad, Georges Stamatakis, Geraldine Cazajous, Geraldine D'ythurbide, Geraldine Robitaille Wiart, Gerard Cardon, Gerard Champion, Gerard Deschodt, Gerard Mangenot, Gerard Motte, Gerard Schortgen, Ghada Boulahia, Ghassan Maakaroun, Ghylene Bourdat Michel, Gilbert Zanetta, Gilles Hufnagel, Gilles Messier, Giorgina Piccoli, Gregoire Couvrat Desvergnes, Guillaume Bobrie, Guillaume Bonnard, Guillaume Clement, Guillaume Jean, Guillaume Queffeulou, Guillaume Seret, Guillaume Vernin, Guy Delavaud, Guy Lambrey, Guy Rostoker, Gwenaelle Poussard, Gwenaelle Roussey Kesler, H. Leon, Habib Aboubekr, Hacene Boulechfar, Hacene Sekhri, Hadia Hebibi, Hadjira Benalia, Hafed Fessi, Hafsabhai Atchia, Haiat Bittar, Hakim Maiza, Hakim Mazouz, Hamid El Ali, Hammouche Bougrida, Hans Van Der Pijl, Hassan Lokmane, Hassane Izzedine, Hassen Adda, Helene De Preneuf, Helene Leray, Helene Philippot, Henri Boulanger, Henri Merault, Henri Renaud, Herve Bonarek, Herve Maheut, Hilaire Nzeyimana, Hocine Mehama, Hocine Zaidi, Hugo Weclawiak, Hugues Flodrops, Huseyin Karaaslan, Ibrahim Haskour, Ihssen Belhadj, Imad Almoubarak, Imad Haddad, Ines Castellano, Ines Ferrandiz, Ioana Daniliuc, Ioana Darie, Ioana Enache, Ionut Prunescu, Irenee Djiconkpode, Irina Shahapuni, Isabelle Bouchoule, Isabelle Devriendt, Isabelle Kazes, Isabelle Kolb, Isabelle Landru, Isabelle Poli, Isabelle Rey, Isabelle Segalen, Isabelle Selcer, Isabelle Vernier, Isabelle Vrillon, Ismahane Guenifi, J. Dominique Gheerbrandt, Jacky Potier, Jacques Becart, Jacques Cledes, Jacques Ducros, Jacques Duvic, Jacques Fourcade, Jacques Gaultier, Jacques Jurine, Jacques Lebleu, Jacques Ollier, Jacques Ibsen Charles, Jamal Yazji, Janette Mansour, Jean Arnautou, Jean Brocard, Jean Carolfi, Jean Montoriol, Jean Baptiste Gouin, Jean Bernard Palcoux, Jean Christophe Bendini, Jean Claude Aldigier, Jean Claude Alphonse, Jean Daniel Delbet, Jean Francois Bonne, Jean Francois Cantin, Jean Francois De Fremont, Jean Francois Dessassis, Jean Francois Subra, Jean Francois Valentin, Jean Francois Verdier, Jean Jacques Dion, Jean Jacques Haultier, Jean Jacques Montseny, Jean Louis Bacri, Jean Louis Bouchet, Jean Luc Mahe, Jean Marc Chalopin, Jean Marc Gabriel, Jean Marc Hurot, Jean Marc Lanau, Jean Marie Batho, Jean Marie Coulibaly, Jean Michel Hardin, Jean Michel Marc, Jean Michel Poux, Jean Michel Rebibou, Jean Michel Tivollier, Jean Noel Ottavioli, Jean Paul Faucon, Jean Paul Imiela, Jean Paul Jaulin, Jean Paul Masselot, Jean Paul Ortiz, Jean Philippe Bourdenx, Jean Philippe Devaux, Jean Philippe Hammelin, Jean Pierre Rivory, Jean Pierre Wauquier, Jean Rene Larue, Jean Rene Mondain, Jean Sebastien Borde, Jean Simon Virot, Jean Yves Bosc, Jedjiga Achiche, Jennifer Parasote, Jeremie Diolez, Jerome Harambat, Jerome Potier, Jerome Sampol, Jihad Mustel, Jean Jacques Lefevre, Jocelyne Maurizi, Joel Gamberoni, Joelle Claudeon, Joelle Terzic, Joffrey Rogol, Johnny Sayegh, Jorge Cardozo, Jose Brasseur, Jose Guiserix, Joseph Barsumau, Julie Albaret, Julie Beaume, Julie Sohier Attias, Julien Dehay, Julien Hogan, Julien Journet, Julien Ott, Juliette Baleynaud, Justine Bacchetta, Justine Faucher, Kamel Yousfi, Karim Dardim, Karine Clabault, Karine Moreau, Kedna Thomas, Khaled Sirajedine, Khalil Chedid, Khalil El Kaeoui, Khalil El Karoui, Khedidja Bouachi, Kheira Hue, Khuzama El Nasser, Kodso Akposso, Kristian Kunz, Krzysztof Bijak, Lilia Kihal, L. Rasoloarijaona, Laid Harbouche, Larbi Bencheikh, Larbie Lamriben, Latifa Hanafi, Laura Braun Parvez, Laure Champion, Laure Croze, Laure Eprinchard, Laure Patrier, Laurence Nicolet, Laurence Vrigneaud, Laurent Duflot, Leandre Mackaya, Leila Chenine, Leon Odry, Lili Taghipour Tamiji, Lilia Antri Bouzar, Liliane Ngango Nga Messi, Lionel Le Mouellic, Lise Mandart, Lise Weis, Lise Marie Pouteau, Lora Georgieva, Lorita Vitanova, Lotfi Chalabi, Luc Delvallez, Luc Fromentin, Luc Marty, Luc Monjot, Luciana Spataru, Lucie Bessenay, Lucie Boissinot, Lucie Wajsbrot, Lucien Rakoff, Ludivine Lebourg, Lydie Perez, Lyliane Lafage, Lynda Azzouz, Madeleine Dumoulin, Messaoud Ouziala, Maan Joseph, Mabrouk Brahimi, Maeva Wong Fat, Magalie Fort, Magued Nakhla, Mahdi Abtahi, Mahen Albadawy, Mahmoud Alouach, Mahmoud Mezghani, Maite Daroux, Maklouf Boukelmoune, Malek Dhib, Malik Touam, Malina Dubau, Mamadou Balde, Man Nguyen Khoa, Manfred Ismer, Manolie Mehdi, Manon Laforet, Marc Bouiller, Marc Eugene, Marc Fila, Marc Hazzan, Marc Kribs, Marc Ladriere, Marc Lebot, Marc Padilla, Marc Souid, Marcel Marraoui, Maren Burbach, Maria Manescu, Maria Eugenia Noguera Gonzalez, Mariana Revenco, Marianne Terrasse, Marie Essi, Marie Alice Macher, Marie Beatrice Nogier, Marie Cecile Cazin, Marie Christine Schweitzer Camoin, Marie Christine Thouret, Marie Claude Hannaert, Marie France Servel, Marie Helene Chabannier, Marie Jeanne Coudert Krier, Marie Noelle Catoliquot, Marie Paule Guillodo, Marie Sophie Gavard, Marie Xaviere Vairon Codaccioni, Marina Rabec, Marine Freist, Marion Gauthier, Marion Lemaire, Marion Mehrenberger, Marion Venot, Marios Pongas, Marlene Beaubrun Diant, Martial Levannier, Martine Bertaux, Mathieu Jablonski, Mathieu Sacquepee, Mathilde Dargelos, Mathilde Lemoine, Mathilde Tamain, Matthieu Monge, Matthieu Reberolle, Maud Cousin, Maud Francois, Maurice Baron, Maxime Hoffmann, Maxime Ingwiller, Maxime Touzot, Mederick Mohajer, Mehadji Maaz, Melanie Hanoy, Melanie Marroc, Melodie Cuny, Menno Van Der Straaten, Mf. Serveaux, Michel Basteri, Michel Fen Chong, Michel Hecht, Michel Massad, Michel Normand, Michel Olmer, Michel Tolani, Michel Tsimaratos, Michele Hemery, Michele Kessler, Miguel Esposito, Milad Shenouda, Mimi Kareche, Mina Khalili, Mirella Diaconita, Mohamad Khair Rifard, Mohamed Aladib, Mohamed Belmouaz, Mohamed Brahim, Mohamed Diouani, Mohamed Fodil Cherif, Mohamed Jamali, Mohamed Maghlaoua, Mohamed Meddeb, Mohamed Ramdane, Mohamed Rifaat, Mohamed Sharifull Islam, Mohamed Adnan Abbade, Mokhtar Amrandi, Mokhtar Chawki, Monica Ciobotaru, Monica Indrieis, Monique Chanas, Monique Hoarau, Monzer Tomeh, Moufida Bellou, Mouloud Bouzernidj, Mounia Ammor, Mounir Guergour, Mountassir Benzakour, Mourad Hachicha, Moussa Coulibaly, Mustafa Smati, Mustapha Al Morabiti, Mustapha Amirou, Myriam Isnard, Myriam Pastural, Myriam Pujo, Nourredine Boumendjel, Nabil Majbri, Nabila Goumri, Nadege Mingat, Nader Bassilios, Nadia Kerkeni, Nadia Sedrati, Nadia Soltani, Nadine Maroun, Nadine Neyrat, Nahn Luang, Najeh El Esper, Naji Ammar, Nasredine Ghali, Nasser Hamdini, Natacha Noel, Natacha Potelune, Nathalie Maisonneuve, Nathalie Pertuiset, Nathalie Raynal, Nathalie Vittoz, Nazim Terki, Nelly Castin, Nestor Nankeu, Nicolas Bouvier, Nicolas Keller, Nicolas Legros, Nicolas Peters, Nicolas Quirin, Nicole Lefrancois, Nicole Monnier, Nicole Rance, Niels Bruckmann, Noel Mertens, Nolwenn Lorcy, Olivia Gilbert, Olivier Coldefy, Olivier Drouineau, Olivier Dunand, Olivier Fritz, Olivier Imhoff, Olivier Kourilsky, Olivier Lavelle, Olivier Papin, Olivier Roques, Ophelie Le Maner, Oussamah Fikri Benbrahim, Pablo Antonio Erina Torres, Pablo Antonio Urena Torres, Paolo Malvezzi, Pascal Bindi, Pascal Cluzel, Pascal Fontanier, Pascal Wheatley, Pascale Depraetre, Pascale Dubosq, Pascale Halin, Pascale Sebahoun, Pascale Siohan, Pascale Testevuide, Patrice Deteix, Patrice Nolen, Patricia Hue, Patricia Lemarchand, Patrick Donnadieu, Patrick Fievet, Patrick Fohrer, Patrick Francais, Patrick Giraud, Patrick Hallonet, Patrick Henri, Patrick Michaut, Patrick Niaudet, Patrick Pauly, Patrick Thomas, Patrik Deleaval, Paul Finielz, Paul Stroumza, Paule Hardy Yverneau, Pauline Caillard, Pedro Palacin, Perrine Aubertin, Philippe Attias, Philippe Chauveau, Philippe Coindre, Philippe Coste, Philippe Dubot, Philippe Fournier, Philippe Hiernaux, Philippe Jousset, Philippe Lan Yue Wah, Philippe Lang, Philippe Le Cacheux, Philippe Martin Dupont, Philippe Michel, Philippe Mirgaine, Philippe Moriniere, Philippe Nicoud, Philippe Rieu, Philippe Rousseau, Philippe Sporer, Philippe Thorel, Philippe Vanhille, Philippe Vigeral, Philippe Zaoui, Pierre Bataille, Pierre Brignon, Pierre Filipozzi, Pierre Housset, Pierre Peyronnet, Pierre Ramperez, Pierre Vautrin, Pierre Alexandre Michel, Pierre Francois Westeel, Pierre Louis Carron, Pierre Yves Durand, Pierrot Parent, Piotr Seniuta, François Kuentz, Rabah Fraoui, Rachel Tetaz, Rachid Amaria, Rachid Bourouma, Rachid Djeffal, Rachida Nebbad, Radia Allal, Radu Dimulescu, Rafaat Boustani, Rafik Mesbah, Raifat Makdassi, Raji Diab, Raluca Puslenghea, Raoul Roura, Rateb Khayat, Raymond Azar, Raymond Frayssinet, Regine Monkam, Rehouni Boulahrouz, Remi Boudet, Renato Demontis, Renaud Gansey, Rene Cuvelier, Renee Schmitt, Reschad Noordally, Reynald Binaut, Rezkallah Latif, Richard Dufresne, Richard Montagnac, Richard Reade, Robert Genin, Robert Novo, Rocsana Fickl, Roger Dufresne, Roger Magnol, Roland Issautier, Romain Mortelette, Ronan Delaval, Ronan Lohro, Roseline M'barga, S. Beau, Clémentine Dupuis, Marie Jacques Vidil, Sabria Hacini, Said Dahmoune, Saliha Lekhal, Salima Ahriz Sakso, Salima Saksi, Salvatore Citarda, Samir Boubenider, Samuel Kassis, Sandra Verhille, Sandrine Genestier, Sandrine Muller, Saoussen Krid, Sarah Richter, Sebastien Delbes, Sebastien Mailliez, Sebastien Veillon, Sébastien Nony, Seddick Benarbia, Severine Beaudreuil, Sidi Ali Benyaghla, Simon Duquennoy, Simona Baluta, Simona Boncila, Sonia Mzoughi, Sonia Ribal, Sophie Acamer, Sophie Chauvet, Sophie Girerd, Sophie Ozenne, Sophie Parahy, Sophie Rubens Duval, Sophie Taque, Soraya Menouer, Soumaya Chargui, Stanislas Bataille, Stephane Barbier, Stephane Billion, Stephane Roueff, Stephane Torner, Stephane Jean Martin, Stephanie Coupel, Sylvie Cloarec, Sylvie Lavaud, Sylvie Leou, T. Chatelet, Tania Onesta, Tassadit Benhabib, Tayeb Bensalem, Theodora Dimulescu, Theophile Sawadogo, Thibault Dolley Hitze, Thierry Baranger, Thierry Boudemaghe, Thierry Hannedouche, Thierry Krummel, Thierry Milcent, Thomas Dervaux, Thomas Guincestre, Thomas Kofman, Thomas Raphael, Thomas Sadreux, Tim Ulinski, Tiphaine Guyon Roger, Tomas Serrato, Tomek Kofman, Tony Wong, Toufik Boubia, Ubald Assogba Gbindoun, Usama Khuzaie, Valerie Caudwell, Valerie Chatelet, Valerie Crougneau, Valerie De Precigout, Valerie Drouillat, Valerie Galantine, Valerie Granveau Hugot, Valerie Leroy, Veronique Boubia, Veronique Falque, Veronique Fournier, Veronique Queron, Veronique Viviani, Victor Gueuttin, Victor Panescu, Victorio Menoyo Calonge, Viet Nguyen, Vincent Allot, Vincent Delattre, Vincent Leduc, Vincent Pradier, Violaine Emal Aglae, Viorica Badulescu, Virginia Molina, Virginie Besson, Virginie Chaigne, Waddah Jaber, Wael Boudi, Wael El Haggan, Wen Qin Guillon, Wided Tabbi Aneni, William Hanf, Wladimir Kohn, Xavier Bellenfant, Xavier Moreau Gaudry, Yahsou Delmas, Yannick Knefati, Yannick Saingra, Yannick Tirolien, Youssef Mann, Yvan Brunak, Yves Dimitrov, Yves Doussy, Yves Tanter, Zaid Benabid, Zaara Soltani, Zacharia Boukerroucha, Zafer Takla, Zana Ramanantsialonina, Zara Dickson, Zead Tubail, Zoe Koochaki Pour, Zohra Boukhalfa, Zohra Jacquot, Agence de la biomédecine [Saint-Denis la Plaine], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Caen Normandie (UNICAEN), Normandie Université (NU), CALYDIAL Vienne, Partenaires INRAE, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Armand Trousseau [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'Epidémiologie et Evaluations Cliniques [CHRU Nancy] (Pôle S2R), Centre Universitaire des Maladies Rénales [CHU Caen] (CUMR Caen), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Assistance Publique - Hôpitaux de Marseille (APHM), Service de diabétologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Service de Diabétologie [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Hemodialysis, Home, Disease, MESH: COVID-19 / therapy, registry, Ambulatory Care Facilities, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Aged, 80 and over, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, 80 and over, Prevalence, covid, dialysis, epidemiology, mortality, Aged, Aged, 80 and over, COVID-19, Case-Control Studies, Critical Care, Female, France, Humans, Incidence, Middle Aged, Patient Acuity, Protective Factors, Registries, Renal Dialysis, SARS-CoV-2, Sex Factors, Hypoalbuminemia, MESH: France / epidemiology, education.field_of_study, Incidence (epidemiology), 3. Good health, MESH: COVID-19 / epidemiology, Nephrology, Hemodialysis, medicine.medical_specialty, Population, Lower risk, Article, 03 medical and health sciences, MESH: Sex Factors, Internal medicine, medicine, MESH: SARS-CoV-2, MESH: Renal Dialysis / statistics & numerical data, education, Dialysis, Vascular disease, business.industry, medicine.disease, Former Smoker, MESH: Critical Care / statistics & numerical data, 030104 developmental biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Home, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Hemodialysis, Home / statistics & numerical data
Abstract: The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed., Graphical abstract
Published: 2020
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3. Asymmetric muscle weakness due to

Author: Xavière, Lornage, Susana, Quijano-Roy, Helge, Amthor, Robert-Yves, Carlier, Nicole, Monnier, Jean-François, Deleuze, Norma B, Romero, Jocelyn, Laporte, and Johann, Böhm
Subjects: Muscle Weakness, Electromyography, Mosaicism, Biopsy, Exome Sequencing, Mutation, Missense, Humans, Child, Magnetic Resonance Imaging, Actins, Pedigree
Abstract: To characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.The patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy.Both patients presented with early-onset hypotonia, delayed motor milestones, scoliosis, and reduced pulmonary function. Patient P1 manifested unilateral muscle weakness exclusively affecting the left side of the body; the asymmetry was less pronounced in patient P2. Muscle biopsies from both patients showed nemaline rods as the main histopathologic hallmark, and MRI revealed major fatty infiltrations in selective head, proximal, and distal muscles, correlating with the degree of muscle weakness asymmetry. Exome sequencing on blood DNA from both patients identified de novoDe novo mutations can occur anytime during embryonic development and may result in a mosaic pattern of affected cells and tissues and lead to the development of an asymmetric clinical picture. The present study points out that mosaic mutations might not be easily detectable on leukocyte DNA and thereby escape routine genetic analysis, and possibly account for a significant number of molecularly undiagnosed patients.
Published: 2020

4. Asymmetric muscle weakness due to ACTA1 mosaic mutations

Author: Johann Böhm, Jocelyn Laporte, Helge Amthor, Norma B. Romero, Robert-Yves Carlier, Susana Quijano-Roy, Jean-François Deleuze, Xavière Lornage, Nicole Monnier, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Sanger sequencing, Mutation, Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Muscle weakness, medicine.disease_cause, Genetic analysis, Hypotonia, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, 0302 clinical medicine, Biopsy, symbols, Medicine, Missense mutation, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Exome sequencing, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: ObjectiveTo characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.MethodsThe patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy.ResultsBoth patients presented with early-onset hypotonia, delayed motor milestones, scoliosis, and reduced pulmonary function. Patient P1 manifested unilateral muscle weakness exclusively affecting the left side of the body; the asymmetry was less pronounced in patient P2. Muscle biopsies from both patients showed nemaline rods as the main histopathologic hallmark, and MRI revealed major fatty infiltrations in selective head, proximal, and distal muscles, correlating with the degree of muscle weakness asymmetry. Exome sequencing on blood DNA from both patients identified de novo ACTA1 missense mutations in a small number of reads, suggesting mutation mosaicism. Subsequent Sanger sequencing confirmed the presence of the mutations on muscle DNA, while they were barely detectable on blood DNA.ConclusionsDe novo mutations can occur anytime during embryonic development and may result in a mosaic pattern of affected cells and tissues and lead to the development of an asymmetric clinical picture. The present study points out that mosaic mutations might not be easily detectable on leukocyte DNA and thereby escape routine genetic analysis, and possibly account for a significant number of molecularly undiagnosed patients.
Published: 2020
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5. A novel large deletion in the RYR1 gene in a Belgian family with late-onset and recessive core myopathy

Author: Marc Abramowicz, Gauthier Remiche, Hazim Kadhim, Joël Lunardi, Nicolas Mavroudakis, and Nicole Monnier
Subjects: Adult, Male, Late onset, Biology, Bioinformatics, Compound heterozygosity, medicine.disease_cause, White People, Late Onset Disorders, Young Adult, Belgium, Muscular Diseases, medicine, Humans, Family, Myopathy, Gene, Genetics (clinical), Aged, Aged, 80 and over, Inclusion Bodies, Genetics, RYR1, Mutation, Ryanodine Receptor Calcium Release Channel, Middle Aged, musculoskeletal system, medicine.disease, Phenotype, Pedigree, Neurology, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), medicine.symptom, Gene Deletion, Central core disease
Abstract: We report a novel and particularly unusual type of mutation, namely, large deletion in the RYR1 gene, in a Belgian family with myopathy: Patients were found to be compound heterozygous and presented a clinico-pathological phenotype characterized by late-onset and recessive myopathy with cores. We depict the clinical, electrophysiological, pathological and molecular genetic characteristics of family members. To date, large deletions in the RYR1 gene have been reported in only two cases. Both involved different mutations and, in sharp contrast to our cases, presented with a very early-onset, neonatal, and a very severe or lethal phenotype. Overview of reported clinico-pathologic phenotypes, also highlights the rarity of combined late-onset/recessive co-occurrence in this group of myopathies with cores. Finally, this report underlines the broadening spectrum in this group of myopathologic disorders and highlights the concept of 'RYR1-associated/related core myopathies'.
Published: 2015
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6. 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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7. Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations inTPM2andTPM3Causing Congenital Myopathies

Author: Nigel F. Clarke, Michèle Mayer, Willie Stewart, Carina Wallgren-Pettersson, Ricardo Reisin, Marion Gérard, Steven B. Marston, Cheryl Longman, Moshe Frydman, Vilma-Lotta Lehtokari, Marianne de Visser, Enrico Bertini, Jacob S. Hogue, Tuula A. Nyman, Mikaela Grönholm, Eugenio Mercuri, Brigitte Gilbert-Dussardier, Katarina Pelin, Alan H. Beggs, Kristen J. Nowak, Sylviane Peudenier-Robert, Tom L. Winder, Helena Pihko, Frank J. Probst, Ekkehard Wilichowski, Ana Lia Taratuto, OÖzge Ceyhan-Birsoy, Hans Lochmüller, Nicole Monnier, Christine Barnerias, John B Winer, M. Marttila, Hanna Kolski, Pascal Cintas, Kathryn N. North, Nigel G. Laing, Lars Klinge, Bruno Eymard, Peter B. Kang, Laurent Magy, Véronique Manel, and Neurology
Subjects: hypercontractile phenotype, Male, Tropomyosin, medicine.disease_cause, TPM2, 0302 clinical medicine, Nemaline myopathy, congenital myopathy, Databases, Genetic, Phosphorylation, Child, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Skeletal, Phenotype, 3. Good health, Child, Preschool, Muscle, Female, medicine.symptom, actin, Protein Binding, Adult, Adolescent, Molecular Sequence Data, genotype-phenotype correlation, Biology, Article, Young Adult, Databases, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Muscular Diseases, Genetic, medicine, Humans, Amino Acid Sequence, Muscle, Skeletal, Preschool, Myopathy, Genetic Association Studies, Actin, 030304 developmental biology, Infant, medicine.disease, Congenital myopathy, Actins, TPM3, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.
Published: 2014
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8. K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

Author: Mikaela Grönholm, M. Marttila, Biljana Ilkovski, Nigel F. Clarke, Elyshia McNamara, Dominique Menard, Massimiliano Memo, Nicole Monnier, Elina Lemola, Carina Wallgren-Pettersson, Jill Trewhella, Jens Reimann, Steve Marston, Coen A.C. Ottenheijm, Andoni Echaniz-Laguna, Nancy Mokbel, Nan Yang, Cy M. Jeffries, Vilma-Lotta Lehtokari, Michaela Kreissl, Mariz Vainzof, Kristen J. Nowak, Kathryn N. North, Nigel G. Laing, Pascale Marcorelles, Gianina Ravenscroft, Physiology, and ICaR - Heartfailure and pulmonary arterial hypertension
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Swine, Molecular Sequence Data, Muscle Fibers, Skeletal, Tropomyosin, macromolecular substances, Biology, Gene mutation, Myopathies, Nemaline, Sarcomere, TPM2, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Nemaline myopathy, Internal medicine, Secondary Prevention, medicine, Animals, Humans, PROTEÍNAS MUSCULARES, Amino Acid Sequence, Cells, Cultured, Genetic Association Studies, Actin, Aged, 030304 developmental biology, 0303 health sciences, Genetic Carrier Screening, Skeletal muscle, Middle Aged, medicine.disease, Congenital myopathy, Pedigree, Rats, medicine.anatomical_structure, Endocrinology, Biochemistry, Mutation, Calcium, Female, Neurology (clinical), Chickens, 030217 neurology & neurosurgery
Abstract: Mutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved lysine residue near the N-terminus of β-tropomyosin, which is predicted to disrupt head-to-tail polymerization of tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the troponin/tropomyosin-dependent calcium switch of muscle. Joint contractures may stem from chronic muscle hypercontraction due to increased myofibrillar calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from therapies that reduce skeletal muscle calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity. * Abbreviations : CCD : charge-coupled device CD : circular dichroism DTT : dithiothreitol EGFP : enhanced green fluorescent protein EGTA : ethylene glycol-bis tetraacetic acid IPG : immobilised pH gradient K7del-βTm : K7del-β-tropomyosin recombinant protein MES : morpholinoethanesulfonic acid NADH-TR : nicotinamide adenine dinucleotide hydroxyl tetrazolium reductase NHLBI : The National Heart Lung and Blood Institute SAXS : small-angle X-ray scattering WT-βTm : wild-type β-tropomyosin
Published: 2013
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9. 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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10. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization

Author: Annie Laquerrière, Soledad Monges, Jorge A. Bevilacqua, Joël Lunardi, Ana Ferreiro, Fabiana Lubieniecki, Nicole Monnier, Kristin Claeys, Ana Lia Taratuto, Isabelle Marty, Michel Fardeau, Marcus Bitoun, Pascale Guicheney, Norma B. Romero, and Bruno Eymard
Subjects: Pathology, medicine.medical_specialty, Histology, Biology, Compound heterozygosity, medicine.disease_cause, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), medicine, Myopathy, 030304 developmental biology, RYR1, 0303 health sciences, Mutation, Muscle biopsy, medicine.diagnostic_test, Malignant hyperthermia, musculoskeletal system, medicine.disease, Congenital myopathy, 3. Good health, Neurology, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Central core disease
Abstract: J. A. Bevilacqua, N. Monnier, M. Bitoun, B. Eymard, A. Ferreiro, S. Monges, F. Lubieniecki, A. L. Taratuto, A. Laquerriere, K. G. Claeys, I. Marty, M. Fardeau, P. Guicheney, J. Lunardi and N. B. Romero (2011) Neuropathology and Applied Neurobiology37, 271–284 Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization Aims: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Methods: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Results: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Conclusion: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.
Published: 2011
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11. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency

Author: Denise Ponard, Anette Bygum, Nicole Monnier, Joël Lunardi, Christian Drouet, and Christina Fagerberg
Subjects: medicine.medical_specialty, Immunology, Population, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Genotype, DNA Mutational Analysis, Immunology and Allergy, Medicine, education, Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, business.industry, Genetic heterogeneity, Autosomal dominant trait, medicine.disease, 3. Good health, 030228 respiratory system, Hereditary angioedema, business
Abstract: To cite this article: Bygum A, Fagerberg CR, Ponard D, Monnier N, Lunardi J, Drouet C. Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. Allergy 2011; 66: 76–84. Abstract Background: Hereditary angioedema (HAE), type I and II, is an autosomal dominant disease with deficiency of functional C1 inhibitor protein causing episodic swellings of skin, mucosa and viscera. HAE is a genetically heterogeneous disease with more than 200 different mutations in the SERPING1 gene. A genotype–phenotype relationship does not seem to exist in HAE, although the polymorphism c.-21T>C of exon 2 has been reported to be associated with a more severe phenotype. We aimed to establish the mutational spectrum of C1 inhibitor deficiency in Denmark and investigate the possible disease-aggravating effect of the c.-21T>C polymorphism. Methods: Hereditary angioedema was diagnosed based on clinical features and C1 inhibitor deficiency. A general severity score ranging from 0 to 10 was developed based on age at disease onset, clinical manifestations and treatment experiences. SERPING1 gene investigation was performed by exon sequencing followed by multiplex ligation-dependent probe amplification genomic rearrangement analysis in all known Danish HAE families. Results: Fifty-nine patients with HAE from 26 families were included in this study. The mean disease severity score was 7.12 [1–10], and the mean C1 inhibitor function was 26% [20–46%]. The sensitivity of the mutational screening was 96%, and 13 new mutations were found in this Danish patient cohort. Nine patients (15%) carried the c.-21T>C polymorphism, but they didn’t have a more severe phenotype. Conclusion: Thirteen new mutations were identified in the Danish HAE population. No correlation between the c.-21T>C polymorphism, the biochemical values of C1 inhibitor function and the clinical severity score was found.
Published: 2010
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12. 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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13. Multiphasic effects of blood pressure on survival in hemodialysis patients

Author: Thierry Hannedouche, Hubert Roth, Thierry Krummel, Gérard M. London, Guillaume Jean, Jean-Louis Bouchet, Tilman B. Drüeke, Denis Fouque, Lahcene Attroun, Raymond Azar, Pierre Bories, Agnès Caillette-Beaudouin, Bernard Canaud, Gabriel Choukroun, Vincent Esnault, Mohamed Hammadi, Patrick Henri, Philippe Honoré, Belkacem Issad, Dominique Joly, Eric Laruelle, Gildas Le Mao, Sylvain Marchais, Benoît Vendrely, Philippe Zaoui, Larbi Aazib, Abdelhamid Abbassi, Elias Abdullah, Habib Abou-Bekr, Carine Achard-Hottelart, Geneviève Achin, Salima Ahriz-Saksi, Mahen Albadawy, Catherine Albert, Samir Albitar, Farideh Alenabi, Mahmoud Allouache, Amar Amaouche, Brahim Amara, Mounia Ammor, Kim Seng Ang, Ubald Assogba, Lynda Azzouz, Chérif Badid, Juliette Baleynaud, Evelyne Bargas, Emmanuel Baron, François Basse, Jean-Marie Batho, Marc Bauwens, Dorothée Bazin, Abdelmajid Ben Aicha, Seddik Benarbia, Larbi Bencheikh, Jean-Christophe Bendini, Djeleddine Benyakoub, Dominique Bergua, Catherine Bessin, Luc Billaux, Stéphane Billion, Haïat Bittar, Jean-Paul Bocquet, Hervé Bonarek, Claude Bonniol, Jean-Sébastien Borde, Samir Boubenider, Rémi Boudet, Waël Boudi, Loreley Boudier, Djema Bouguern, M Boukelmoune, Fatha Zohra Boukhalfa, Henri Boulanger, Philippe Bouvier, Mouloud Bouzernidj, Mohamed Brahim Bounab, José Brasseur, Laura Braun, Marie Briet, Doan Bui-Quang, Sebastien Canet, Eric Canivet, Jorge Cardozo, Carlos Cardozo, Baher Chaghouri, Mokhtar Chawki, Charles Chazot, Philippe Choulet, Pierre Clavel, Jean-Philippe Coindre, Olivier Coldefy, M.A. Colomina, François Combarnous, Christian Dabot, Djamal Dahmane, Ahmed Dahmani, Daniel Daubresse, Jean-François De Fremont, Valérie De Precigout, Françoise Dehais, M. Dehina, Caroline Delclaux, Yashou Delmas, Coralia Denicola, Jean-Philippe Devaux, Raji Diab, Zineddine Diddaoui, null Didelot, Yves Dimitrov, Assia Djema, Patrick Donnadieu, Valérie Drouillat, Olivier Drouineau, Geneviève Dumont, Philippe Dupuy, Pierre-Yves Durand, Stéphane Edet, Hamid El Ali, Khuzama El Nasser, Christian Emond, Baya Fadel, Mohamed Fakir, Jean-Paul Faucon, André Faure, Assia Ferhat-Carre, Hafedh Fessi, Rocsana Fickl, Mahammed Fodil-Cherif, Jacques Fourcade, Philippe Fournier, Rabah Fraoui, Olivier Fritz, Elke Gaboriau, Alexandre Ganea, Roula Galland, Jacqes Gaultier, Eric Gauthier, Sylvie Geffroy Guiberteau, Sandrine Genestier, Patrick Giraud, Françoise Glowacki, Christophe Goupy, Pierre Grimal, Mounir Guergour, Jean Gugliotta, Marie-Paule Guillodo, Marie-Claude Guimont, Toufic Hachache, Sabria Hacini, Imad Haddad, Mohamed Hadj-Abdelkader, Pascale Halin, Patrick Hallonet, Nasser Hamdini, Didier Hamel, Françoise Heibel, Alain Hermelin, Alim Heyani, Philippe Hiernaux, Maxime Hoffmann, Valérie Hugot, Richard Ibos, Dominque Jacq, Jean-Paul Jaulin, Philippe Jousset, Benoît Jonon, Véronique Joyeux, Laurent Juillard, Amer Kamal, Mimi Kareche Chibout, Rateb Khayat, Franklin Khazine, Karim Khellaf, Arnaud Klisnick, Yannick Knefati, A. Kolko-Labadens, Amir Kolta, Niloufar Kossari, Olivier Kourilsky, Nicolas Krayem, Marc Kribs, François Kuentz, Kristian Kunz, Christian Lamotte, Jean-Marc Lanau, Isabelle Landru, Achour Laradi, Nicole Larroumet, Olivier Lavelle, Frank Le Roy, Alejandra Lenz, Denis Lerda, Fanny Leroy, Marc Leteif, Martial Levannier, Thierry Lobbedez, Hassan Lockmane, Nathalie Longlune, Christie Lorriaux Mortuaire, Alain Lyon, Ghassan Maakaroun, Mehadji Maaz, Eric Magnant, Ghandour Majdalani, Jean-Luc Mahe, Edward Maksour, Stéphane Martin, Catherine Martinat-Calvo, Valérie Masson, Delia May, Claire Maynard, Brice Mayor, Omar Mazouz, Hocine Mehama, Dominique Mercier, Gilles Messier, Robert Milongo, Nicole Monnier, Karine Moreau, Xavier Moreau-Gaudry, Bertrand Morel, Luc Moulonguet Doleris, Alexandre Mouneimne, Catherine Mourey-Epron, Françoise Moussion, Blanca Muniz, J. Mustel, Rachida Nebbad, Fazia Nemmar, Sylvie Neuville, Tien Nguyen-Quang, Patrice Nolen, Michel Normand, Emerson N’Sembani, Jacques Ollier, Jean-Paul Ortiz, Messaoud Ouziala, Bernard Painchart, Pedro Palacin, Josette Pengloan, Franck Perrin, Bruno Perrone, Philippe Petitjean, Dominique Petregne, Jean-Baptiste Philit, Vincent Planquois, Marc Pocheville, Jacky Potier, Jean-Michel Poux, Olivier Puyoo, Catherine Quere-Maurouard, Ahmed Rachi, Anderson Ratsimbazafy, Matthieu Reberolle, Henri Renaud, Bernard Richalet, Sarah Richter, Philippe Rieu, Michel Rince, Odile Rivault, Alain Robert, Jacques Rottembourg, Philippe Rousseau, Sophie Rubens Duval, Christa Roubicek, Piotr Seniuta, Pascal Seris, Irina Shahapuni, Reda Sharobeem, Milad Shenouda, Hélène Sichez Com, Danlèle Simonin, Nadia Soltani, Marc Souid, Hadia Sow, Jean-Christophe Szelag, Catherine Taddei, Zafer Takla, Dominque Teboulle, Jean-Claude Terrat, Patrick Thomas, Adam Tifoura, Jacques Toulon, Dominique Touzard, Pablo Urena Torres, Hans Van der Pijl, Thierry Vanel, Carlos Vela, Isabelle Vernier, Cathy Verove, François Pascal Wambergue, Bassem Wehbe, Maeva Wong-Fat, Fatima Yazbeck, Djamal Yousfi, Maan Youssef, Abdelaziz Ziane, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Manhès, Centre de Rein Artificiel, Centre de traitement des maladies rénales, CTMR Saint-Augustin, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Européen de Nutrition pour la Santé, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Male, medicine.medical_specialty, hypertension, Systole, medicine.medical_treatment, Population, 030232 urology & nephrology, Diastole, Blood Pressure, 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Prehypertension, 03 medical and health sciences, 0302 clinical medicine, cardiovascular disease, Renal Dialysis, Risk Factors, Internal medicine, Medicine, Humans, Prospective Studies, Renal Insufficiency, Chronic, education, Aged, Aged, 80 and over, education.field_of_study, hemodialysis, business.industry, Hazard ratio, Blood Pressure Determination, Middle Aged, 3. Good health, Pulse pressure, Blood pressure, Nephrology, Cardiovascular Diseases, Aortic pressure, Cardiology, Female, Hemodialysis, France, business, Follow-Up Studies
Abstract: International audience; Dialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death.
Published: 2015
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14. 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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15. 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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16. 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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17. Génétique et hyperthermie maligne, où en est-on ?

Author: Nicole Monnier, Joël Lunardi, and Joëlle Lerale
Subjects: Anesthesiology and Pain Medicine, business.industry, Emergency Medicine, Medicine, Emergency Nursing, business
Published: 2005
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18. The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre

Author: Serge Perelman, François Rivier, Nicole Monnier, Sue Malcolm, Sylvie Tuffery-Giraud, D. Recan, Jean-Claude Lambert, Mireille Claustres, Bernard Echenne, Jean Marie Cuisset, Mireille Cossée, Marie Antoinette Voelckel, Sylvie Chambert, Eric Bieth, Christophe Philippe, and Céline Saquet
Subjects: Male, Biopsy, Duchenne muscular dystrophy, DNA Mutational Analysis, Molecular Sequence Data, Nonsense mutation, Federal Government, Bioinformatics, Frameshift mutation, Dystrophin, medicine, Humans, Lymphocytes, RNA, Messenger, Statistics & numerical data, Muscular dystrophy, Referral and Consultation, Chromatography, High Pressure Liquid, Genetics (clinical), Family Health, Genetics, Muscle biopsy, medicine.diagnostic_test, biology, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Muscles, Point mutation, medicine.disease, Muscular Dystrophy, Duchenne, Blotting, Southern, Neurology, Mutation, Pediatrics, Perinatology and Child Health, biology.protein, France, Neurology (clinical), business
Abstract: Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.
Published: 2004
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19. Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond

Author: Peter J. Späth, E. Rusicke, Christoph Bucher, Alvaro Blanch, Olga Roche, Emanuela Pappalardo, István Karádi, Marco Cicardi, Mathias Juers, Inmaculada Martinez-Saguer, Roberto Giacomelli, Pál Novák Kaposi, Anthony J. Castaldo, Erik Waage Nielsen, Roberto Perricone, Arianna Kitzinger, Kalman Fay, Emel Aygören-Pürsün, Carlo Perricone, Christian Drouet, George Füst, Beáta Visy, C. Erik Hack, Vincenzo Penna, Hilary Longhurst, Tímea Kollár, George Harmat, István Nagy, Nicole Monnier, Éva Németh, Jan H. Nuijens, Bettina Fischer, Ursula Rauch, Peter L. Lakatos, Caterina De Carolis, Caroline O'Grady, Edit Takács, Margarita López-Trascasa, Henriette Farkas, Albrecht Gröner, George Szendei, Lilian Varga, Alvin E. Davis, Lennart Truedsson, Béla Fekete, John Jakenfelds, Andrea Zanichelli, Wolfhart Kreuz, Kayla Williams, Lajos Kalmar, Lorenza C. Zingale, Karen Binkley, Christiane Duponchel, Laurence Bouillet, Attila Tordai, Luigi Fontana, Angelo Agostoni, and Konrad Bork
Subjects: APP, Aminopeptidase P, C1, First component of the complement cascade, C4, Fourth component of the complement cascade, MFO, Multifollicular ovary, C1 esterase inhibitor, C1nh, Murine C1 esterase inhibitor gene, MBL, Mannan-binding lectin, NAT, Nucleic acid amplification technique, rtPA, Recombinant tissue-type plasminogen activator, Ecallantide, Icatibant, human SERPING1 protein, Gonadal Steroid Hormones, PCO, Polycystic ovary, AT2, Angiotensin II, Contraceptives, OMIM, Online Mendelian Inheritance in Man (database), rhC1-INH, Recombinant human C1 esterase inhibitor, B19V, Parvovirus B19, FFP, Fresh frozen plasma, LH, Luteinizing hormone, UK, United Kingdom, BVDV, Bovine viral diarrhea virus, FF, (Ovarian) follicular fluid, Complement C1 Inhibitor Protein, MGUS, Monoclonal gammopathies of undetermined significance, AAEE, (Italian) Voluntary Association for the Study, Therapy, and Fight Against Hereditary Angioedema, Oral, medicine.medical_specialty, Hereditary angioneurotic edema, Immunology, HANE, HAE-I, Hereditary angioedema type I, Article, PCT, Primary care trust, Cmax, Maximum concentration, HAV, Hepatitis A virus, NEP, Neutral endopeptidase, Humans, chemically induced angioedema, PREHAEAT, Novel Methods for Predicting, Preventing, and Treating Attacks in Patients with Hereditary Angioedema, Intensive care medicine, HbsAg, Hepatitis B surface antigen, MASP, Mannose-binding protein associated serine protease, medicine.disease, hereditary angioneurotic edema, HANO, C1NH, Human C1 esterase inhibitor gene, Settore MED/16 - Reumatologia, C3, Third component of the complement cascade, chemistry, Mutation, CPV, Canine parvovirus, C1-INH, C1 esterase inhibitor, CCM, Chemical cleavage of mismatches, Complement C1 Inactivator Proteins, angioneurotic edema, C1-inhibitor, chemistry.chemical_compound, CPMP, Committee for Proprietary Medicinal Products, AAE, acquired angioedema, angioedema, C1-INH, HAE, hereditary angioedema, HBV, Hepatitis B virus, BMD, Bone mineral density, Immunology and Allergy, PRV, Pseudorabies virus, Mr, Molecular mass, biology, HAE-II, Hereditary angioedema type II, Estrogen Replacement Therapy, Polycystic ovary, CH50, Total hemolytic complement, 50% cell lysis, HUVS, Hypocomplementemic urticaria-vasculitis syndrome, Hereditary angioedema, medicine.symptom, medicine.drug, AAE, Acquired angioedema, DHPLC, Denaturing HPLC, HAE, Hereditary angioedema, HCV, Hepatitis C virus, OC, Oral contraceptive, HK, High molecular weight kininogen, medicine, Angioedema, Serpins, business.industry, tPA, Tissue-type plasminogen activator, C5, Fifth component of the complement cascade, ACE, Angiotensin-converting enzyme, SSCA, Single-stranded conformational analysis, HRT, Hormone replacement therapy, Angiotensin II, SHBG, Sex hormone binding globulin, biology.protein, HAEA, US HAE Association, C2, Second component of the complement cascade, business, Contraceptives, Oral
Abstract: Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.
Published: 2004
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20. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia

Author: Joël Lunardi, Louis Viollet, Jean Paul Leroy, Anne Cortey, Norma B. Romero, M. Chevallay, Michel Fardeau, and Nicole Monnier
Subjects: Male, Pathology, medicine.medical_specialty, Muscle Hypotonia, Genes, Recessive, Biology, Gene mutation, Internal medicine, medicine, Humans, Abnormalities, Multiple, Myopathy, Central Core, Muscle, Skeletal, Myopathy, Fetal Movement, Kyphoscoliosis, Genes, Dominant, Arthrogryposis, RYR1, Movement Disorders, Infant, Newborn, Ryanodine Receptor Calcium Release Channel, Syndrome, medicine.disease, Hypotonia, Pedigree, Fetal Diseases, Endocrinology, Female, Neurology (clinical), medicine.symptom, Central core disease
Abstract: We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.
Published: 2003
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21. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia

Author: Annick Labarre-Vila, Paulette Mezin, Joël Lunardi, Isabelle Marty, Ana Ferreiro, and Nicole Monnier
Subjects: Male, medicine.medical_specialty, RNA Splicing, Muscle disorder, Biology, Muscular Diseases, Internal medicine, Genetics, medicine, Humans, Point Mutation, Missense mutation, Muscle, Skeletal, Molecular Biology, Genetics (clinical), RYR1, Ophthalmoplegia, Malignant hyperthermia, Skeletal muscle, Ryanodine Receptor Calcium Release Channel, Sequence Analysis, DNA, General Medicine, musculoskeletal system, medicine.disease, Congenital myopathy, Pedigree, medicine.anatomical_structure, Endocrinology, Haplotypes, Female, ITGA7, tissues, Central core disease
Abstract: The ryanodine receptor (RYR1) is an essential component of the calcium homeostasis of the skeletal muscle in mammals. Inactivation of the RYR1 gene in mice is lethal at birth. In humans only missense and in-frame mutations in the RYR1 gene have been associated so far with various muscle disorders including malignant hyperthermia, central core disease and the moderate form of multi-minicore disease (MmD). We identified a cryptic splicing mutation in the RYR1 gene that resulted in a 90% decrease of the normal RYR1 transcript in skeletal muscle. The 14646+2.99 kb A--G mutation was associated with the classical form of MmD with ophthalmoplegia, whose genetic basis was previously unknown. The mutation present at a homozygous level was responsible for a massive depletion of the RYR1 protein in skeletal muscle. The mutation was not expressed in lymphoblastoid cells, pointing toward a tissue specific splicing mechanism. This first report of an out-of-frame mutation that affects the amount of RYR1 raised the question of the amount of RYR1 needed for skeletal muscle function in humans.
Published: 2003
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22. Presence of Two Different Genetic Traits in Malignant Hyperthermia Families

Author: Renée Krivosic-Horber, Hugo Reyford, Yves Nivoche, Nicole Monnier, Joël Lunardi, Pascal Adnet, Geneviève Kozak-Ribbens, and Jean-François Payen
Subjects: Genetics, education.field_of_study, business.industry, Genetic heterogeneity, Haplotype, Population, Malignant hyperthermia, Autosomal dominant trait, medicine.disease, Compound heterozygosity, Anesthesiology and Pain Medicine, Genetic marker, Medicine, Allele, education, business
Abstract: Background Malignant hyperthermia susceptibility (MHS), an uncommon syndrome often inherited as an autosomal dominant trait, is characterized by a genetic and clinical heterogeneity. In this article, the authors described six pedigrees in which both parents of MHS patients were diagnosed with MHS by an diagnostic test. Haplotype and mutation analysis revealed that more than one MHS genetic trait was present in these families. Methods A panel of 104 MHS families were investigated with a caffeine halothane contracture test on muscle biopsy specimens. When possible, blood creatine kinase concentrations of MHS patients were measured. Haplotyping studies were conducted with chromosome 19q13.2 polymorphic markers and mutations were searched for in patients' DNA. Results In six families, the diagnostic test and genetic studies demonstrated that both, apparently unrelated, parents of MHS patients were MHS. In three families, homozygous or compound heterozygous individuals for RYR1 mutations were characterized at a molecular level. In one family, a compound heterozygous patient harboring a RYR1 mutation and a CACNA1S mutation was identified. While patients with two mutated alleles did not show differences in their muscle response to halothane or caffeine, their creatinine kinase concentrations were significantly elevated compared with the heterozygous patients. Conclusions Based on genetic and diagnostic test data, more than one MHS allele associated with the MHS phenotype was evidenced in four families. These data should be considered in view of the use of genetics for the diagnosis of MHS and when reaching conclusions of genetic heterogeneity in MHS families. Taking into account the usual dominant mode of transmission of MHS and the size of the investigated population, the authors propose an evaluation of the incidence of the MHS in the general population based on genetic data.
Published: 2002
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23. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene

Author: Yves Nivoche, Charles-Antoine Haenggeli, Ana Ferreiro, Carsten G. Bönnemann, Nicole Monnier, Norma B. Romero, Arnaud Lemainque, Jean-Paul Leroy, Wolfgang D. Voss, Volker Straub, Heinz Jungbluth, Thomas Voit, Pascale Guicheney, Michel Fardeau, and Joël Lunardi
Subjects: Genetics, 0303 health sciences, education.field_of_study, Pathology, medicine.medical_specialty, Selenoprotein N, Ryanodine receptor, Locus (genetics), Disease, Biology, medicine.disease, Congenital myopathy, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neurology, medicine, Missense mutation, Neurology (clinical), education, 030217 neurology & neurosurgery, Central core disease, 030304 developmental biology
Abstract: Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.
Published: 2002
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24. Hereditary angioedema with F12 mutation: factors modifying the clinical phenotype

Author: Teresa Caballero, Delphine Charignon, Nicole Monnier, Christian Drouet, F. Defendi, Sven Cichon, Kamel Djenouhat, David Launay, Olivier Fain, M. López Trascasa, Denise Ponard, Ludovic Martin, and Arije Ghannam
Subjects: Male, medicine.medical_specialty, Heterozygote, Immunology, Complement C1 Inactivator Proteins, Asymptomatic, Severity of Illness Index, C1-inhibitor, Risk Factors, Internal medicine, Edema, medicine, Odds Ratio, Immunology and Allergy, Humans, Alleles, biology, Catabolism, business.industry, Angioedemas, Hereditary, Odds ratio, Exons, Kinin, medicine.disease, Endocrinology, Phenotype, Case-Control Studies, Hereditary angioedema, Cohort, Factor XII, Mutation, biology.protein, Female, medicine.symptom, business, Complement C1 Inhibitor Protein
Abstract: Background Hereditary angioedema (HAE) with normal C1 inhibitor (C1Inh) associated with the c.983C>A and c.983C>G mutations of the F12 gene (FXII-HAE) is a rare condition, and presents with highly variable clinical expression. On the basis of data gathered from a large carrier cohort, we assessed the modifiers affecting the clinical phenotype. Methods We analyzed clinical and biological data recorded from 118 mutation carriers (80 symptomatic and 38 asymptomatic), 58 noncarrier relatives from 40 families, and 200 healthy donors. Disease severity was scored in relation to frequency and location of edema, as well as age at disease onset. To predict FXII-HAE disease severity, we analyzed the biological phenotype [C1Inh, C4, spontaneous amidase, angiotensin-I-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N/M (CPN)] by means of logistic regression (Akaike information criterion) and odds ratio (OR). Results Meaningful variables contributed to FXII-HAE, with the kinin catabolism enzymes ACE and CPN exhibiting a significant inverse relationship with disease severity (OR = 0.36, 95% CI 0.23–0.59, P
Published: 2014

25. Malignant hyperthermia mutations and correlation with the severity of the anesthetic complication and the level of the in vitro contracture tests

Author: René Krivosic-Horber, Valérie Deken, Nicole Monnier, Anne-Frédérique Dalmas, and Etienne Brasdefer
Subjects: medicine.diagnostic_test, business.industry, Malignant hyperthermia, medicine.disease, Dantrolene, Anesthesiology and Pain Medicine, Anesthesia, Anesthetic, Biopsy, medicine, Oral Presentation, Halothane, Contracture, medicine.symptom, Complication, business, medicine.drug, Muscle contracture
Abstract: Background Malignant hyperthermia (MH) is a complication of anaesthesia appearing as an acute potentially lethal hypermetabolic state in people carrying a genetic anomaly expressed in the skeletal muscle. MH susceptibility can be diagnosed by in vitro contracture test (IVCT) with halothane and caffeine requiring muscular biopsy, or by looking for the MH mutations directly in DNA extracted from the blood. Studies showed an influence of the type of mutation (genotype) on the various expressions (phenotypes) of the MH susceptibility. The aims of this study are to look for any correlation between the presence of a MH mutation and 1) the severity of the anesthetic complication and 2) the force of the contractures observed in the IVCT.
Published: 2014
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26. Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor

Author: L. Karla Arruda, Wagner Narciso de Campos, Joël Lunardi, Faradiba Sarquis Serpa, Denise Ponard, Wilson A. Silva, Marina Mendonça Dias, Alfeu Tavares França, Soloni Afra Pires Levy, Solange Oliveira Rodrigues Valle, Helen Andrade Arcuri, Adriana S. Moreno, Nicole Monnier, Mario Sergio Palma, and Konrad Bork
Subjects: Adult, animal structures, Adolescent, DOENÇAS HEREDITÁRIAS, Immunology, Coagulation Factor XII, Gene mutation, Complement C1 Inactivator Proteins, Polymerase Chain Reaction, C1-inhibitor, Young Adult, medicine, Immunology and Allergy, Humans, Point Mutation, cardiovascular diseases, Allele, Age of Onset, skin and connective tissue diseases, Gene, Alleles, Aged, biology, business.industry, Point mutation, Angioedemas, Hereditary, General Medicine, DNA, Sequence Analysis, DNA, Middle Aged, bacterial infections and mycoses, medicine.disease, Pedigree, Hereditary angioedema, Factor XII, biology.protein, Female, Age of onset, business, Complement C1 Inhibitor Protein, Brazil, circulatory and respiratory physiology
Abstract: Background: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. Methods: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. Results: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. Conclusions: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.
Published: 2014

27. Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene

Author: S. Boucebci, Ursula Schaeffer, Edoardo Malfatti, Michel Fardeau, Norma B. Romero, Jocelyn Laporte, Johann Böhm, Bin Wu, Ting Xie, Nicole Monnier, Fengping Xu, Jean-Philippe Neau, and Stéphane Mathis
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, Neuromuscular disease, Mutation, Missense, Biology, MYOPATHY, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Myopathy, Central Core, Myopathy, Exome sequencing, Aged, RYR1, Genetics, Myosin Heavy Chains, medicine.disease, NEUROPATHOLOGY, MUSCLE, Congenital myopathy, Pedigree, Radiography, Psychiatry and Mental health, Muscle Fibers, Slow-Twitch, Neuromuscular, Surgery, MYH7, Female, Neurology (clinical), MUSCLE DISEASE, medicine.symptom, Cardiac Myosins, Central core disease
Abstract: Background Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families. Objective To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene. Patients and methods Four affected AD family members over three generations, three of whom were alive and participate in the study: the mother and two of three siblings. The symptoms began during the early childhood with mild delayed motor development. Later they developed mainly tibialis anterior weakness, hypertrophy of calves and significant weakness (amyotrophic) of quadriceps. No cardiac or ocular involvement was noted. Results The muscle biopsies sections showed a particular pattern: eccentric cores in type 1 fibres, associated with type 1 predominance. Most cores have abrupt borders. Electron microscopy confirmed the presence of both unstructured and structured cores. Exome sequencing analysis identified a novel heterozygous missense mutation p.Leu1723Pro in MYH7 segregating with the disease and affecting a conserved residue in the myosin tail domain. Conclusions We describe MYH7 as an additional causative gene for AD-CCD. These findings have important implications for diagnosis and future investigations of AD-congenital myopathies with cores, without cardiomyopathy, but presenting a particular involvement of distal and quadriceps muscles.
Published: 2014

28. 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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29. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor

Author: Joëlle Lerale, Joël Lunardi, Norma B. Romero, Yves Nivoche, P. Landrieu, Michel Fardeau, and Nicole Monnier
Subjects: Adult, Male, DNA Mutational Analysis, Molecular Sequence Data, Biology, medicine.disease_cause, Genetics, medicine, Humans, Amino Acid Sequence, Myopathy, Central Core, Allele, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Aged, Family Health, RYR1, Mutation, Binding Sites, Sequence Homology, Amino Acid, Ryanodine receptor, Genetic heterogeneity, Malignant hyperthermia, Ryanodine Receptor Calcium Release Channel, DNA, General Medicine, musculoskeletal system, medicine.disease, Congenital myopathy, Pedigree, Haplotypes, Child, Preschool, Female, tissues, Central core disease
Abstract: Central core disease (CCD) is an autosomal dominant congenital myopathy. Diagnosis is based on the presence of cores in skeletal muscles. CCD has been linked to the gene encoding the ryanodine receptor (RYR1) and is considered to be an allelic disease of malignant hyperthermia susceptibility. However, the report of a recessive form of transmission together with a variable clinical presentation has raised the question of the genetic heterogeneity of the disease. Analyzing a panel of 34 families exclusively recruited on the basis of both clinically and morphologically expressed CCD, 12 different mutations of the C-terminal domain of RYR1 have been identified in 16 unrelated families. Morphological analysis of the patients' muscles showed different aspects of cores, all of them associated with mutations in the C-terminal region of RYR1. Furthermore, we characterized the presence of neomutations in the RyR1 gene in four families. This indicates that neomutations into the RyR1 gene are not a rare event and must be taken into account for genetic studies of families that present with congenital myopathies type 'central core disease'. Three mutations led to the deletion in frame of amino acids. This is the first report of amino acid deletions in RYR1 associated with CCD. According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1.
Published: 2001
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30. 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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31. OCRL1 mutation analysis in French Lowe syndrome patients: Implications for molecular diagnosis strategy and genetic counseling

Author: Véronique Satre, Florence Berthoin, Nicole Monnier, Joël Lunardi, and Eliane Lerouge
Subjects: Male, Oculocerebrorenal syndrome, Genetic counseling, DNA Mutational Analysis, Mutation, Missense, Genetic Counseling, Germline mosaicism, Biology, Frameshift mutation, Exon, Genetics, medicine, Humans, Missense mutation, Frameshift Mutation, Germ-Line Mutation, Genetics (clinical), Sequence Deletion, Mosaicism, Reverse Transcriptase Polymerase Chain Reaction, Haplotype, Proteins, medicine.disease, Phosphoric Monoester Hydrolases, Alternative Splicing, Oculocerebrorenal Syndrome, Codon, Nonsense, Molecular Probes, Female, OCRL, Chromosome Deletion
Abstract: The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked recessively inherited disease characterized by a severe pleiotropic phenotype including mental retardation, bilateral congenital cataract, and renal Fanconi syndrome. The gene responsible for OCRL encodes an inositol polyphosphate-5-phosphatase. We performed mutation analysis in 36 families and characterized 27 new mutations with two of them being recurrent mutations. The panel of mutations consisted of 27 truncating mutations (frameshift, nonsense, splice site mutations, and large genomic deletions), one in-frame deletion, and six missense mutations. The four large genomic deletions occurred in the first half of the gene, whereas all the remaining mutations took place in the second part of the gene and were concentrated in a few exons. This distribution may be of interest in terms of screening strategy when looking for unknown mutations. Haplotyping of the families was performed to analyze segregation of the mutated loci, and revealed a somatic mosaicism in one family. This is the second case of mosaicism we characterized in a total panel of 44 unrelated families affected by Lowe's syndrome. Considering the low number of families investigated, it appeared that somatic and germinal mosaicisms are quite common in this disease and must be taken into account for genetic counseling.
Published: 2000
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32. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France

Author: Francoise Chevalier, C. Verlingue, Isabelle Creveaux, Thierry Bienvenu, Jean-Claude Chomel, Eric Bieth, M.-C. Malinge, Michèle Chery, Perrine Malzac, Albert Iron, Mireille Claustres, C. Guittard, Emanuelle Girodon, Christine Clavel, Nicole Monnier, Claude Férec, Jean-Paul Bonnefont, Martine Blayau, Hervé Mittre, Cécile Cazeneuve, Delphine Feldmann, Viviane Dumur, Marie des Georges, Guy Lalau, and Dominique Bozon
Subjects: Adult, Male, medicine.medical_specialty, Cystic Fibrosis, Genotype, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, medicine.disease_cause, Gastroenterology, Cystic fibrosis, Vas Deferens, Gene Frequency, Internal medicine, Genetics, medicine, Humans, Allele, Frameshift Mutation, Gene, Alleles, Infertility, Male, Genetics (clinical), Mutation, Polymorphism, Genetic, Vas deferens, Middle Aged, medicine.disease, Congenital absence of the vas deferens, Mutagenesis, Insertional, medicine.anatomical_structure, Mutation testing, France, Chromosome Deletion
Abstract: We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7, 420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes. The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies >0. 4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes. We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients. In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78. 90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations.
Published: 2000
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33. Characterization of a Germline Mosaicism in Families with Lowe Syndrome, and Identification of Seven Novel Mutations in the OCRL1 Gene

Author: Isidora López-Pajares, Pierre-Simon Jouk, Henri Jean Philippe, Véronique Satre, María Luisa de Torres, Nicole Monnier, Florence Berthoin, Carmen Ayuso, Alain Joannard, Henri Plauchu, André Megabarne, and Joël Lunardi
Subjects: Male, Heterozygote, Oculocerebrorenal syndrome, Molecular Sequence Data, Nonsense mutation, Germline mosaicism, Biology, Germline, Frameshift mutation, Exon, medicine, Genetics, Humans, Missense mutation, Genetics(clinical), Amino Acid Sequence, Genetic Testing, Genetics (clinical), OCRL, germline mosaicism, Models, Genetic, Sequence Homology, Amino Acid, Mosaicism, Proteins, medicine.disease, mutations, Phosphoric Monoester Hydrolases, Pedigree, Oculocerebrorenal Syndrome, Haplotypes, Mutation, Oculocerebrorenal Lowe syndrome, Female, Microsatellite Repeats, Research Article
Abstract: Summary The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. Mutations in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4,5-biphosphate (PtdIns[4,5]P2) 5-phosphatase. We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein. A missense mutation, R483G, was located in the highly conserved PtdIns(4,5)P2 5-phosphatase domain. Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11–15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This observation has direct implications for genetic counseling of Lowe syndrome families.
Published: 1999
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34. Le récepteur de la ryanodine de type I

Author: Julien Fauré, Joël Lunardi, Isabelle Marty, and Nicole Monnier
Subjects: Ryanodine receptor, Chemistry, General Medicine, Molecular biology, General Biochemistry, Genetics and Molecular Biology
Published: 2008
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35. Cultural Identity and Civil Society in Russia and Eastern Europe: Essays in Memory of Charles E. Timberlake

Author: David M. Borgmeyer, Editor, Nicole Monnier, Editor, Andrew Kier Wise, Editor, David M. Borgmeyer, Editor, Nicole Monnier, Editor, and Andrew Kier Wise, Editor
Abstract: This volume is dedicated to the memory of Charles E. Timberlake. The contributors include his former colleagues and students.The first section deals with “Liberalism and Civil Society in Russia and Eastern Europe.” Alla Barabtarlo discusses unfinished research conducted by Charles Timberlake on the liberal activist Ivan Petrunkevich. Evgeny Badredinov analyzes research on the Russian village conducted by an important liberal lawyer and sociologist, Maksim Kovalevskii. Andrew Wise examines commentary by Polish liberals and their exiled Russian colleagues published in the Warsaw press from 1920–1923.The second section deals with “Orthodoxy and Cultural Identity in Late Imperial Russia.” Robert Nichols explains the role in Russia's monastic revival played by Gethsemane skete, a monastic cloister that was founded in 1844. Sally Stocksdale details the motivations of a self-cloistering Russian noblewoman (Praskovia Yazikova) of the nineteenth century. Jesse Murray explores the cultural and religious identities of residents in the Baikal region. David Borgmeyer focuses on the response to the works of Pablo Picasso by one art critic, Sergei Bulgakov.The third section deals with “Civil Society in the Post-Soviet Era.” Byron Scott demonstrates that press freedom has been a contentious issue in these societies. James McCartney analyzes the reforming of the educational system in independent Georgia.
Published: 2012

36. Malignant-Hyperthermia Susceptibility Is Associated with a Mutation of the a1-Subunit of the Human Dihydropyridine-Sensitive L-Type Voltage-Dependent Calcium-Channel Receptor in Skeletal Muscle

Author: Nicole Monnier, Joël Lunardi, Paul Stieglitz, and Vincent Procaccio
Subjects: RYR1, Genetics, Voltage-dependent calcium channel, Ryanodine receptor, Point mutation, Calcium channel, Malignant hyperthermia, Skeletal muscle, Periodic paralysis, Biology, medicine.disease, Molecular biology, medicine.anatomical_structure, medicine, Genetics(clinical), Genetics (clinical)
Abstract: Summary Malignant hyperthermia susceptibility (MHS) is characterized by genetic heterogeneity. However, except for the MHS1 locus, which corresponds to the skeletal muscle ryanodine receptor (RYR1) and for which several mutations have been described, no direct molecular evidence for a mutation in another gene has been reported so far. In this study we show that the CACNL1A3 gene encoding the a1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC) represents a new MHS locus and is responsible for the disease in a large French family. Linkage analysis performed with an intragenic polymorphic microsatellite marker of the CACLN1A3 gene generated a two-point LOD score of 4.38 at a recombinant fraction of 0. Sequence analysis of the coding region of the CACLN1A3 gene showed the presence of an Arg-His substitution at residue 1086, resulting from the transition of A for G3333, which segregates perfectly with the MHS phenotype in the family. The mutation is localized in a very different part of the a1-subunit of the human skeletal muscle VDCC, compared with previously reported mutations found in patients with hypo-kalemic periodic paralysis, and these two diseases might be discussed in terms of allelic diseases. This report is the first direct evidence that the skeletal muscle VDCC is involved in MHS, and it suggests a direct interaction between the skeletal muscle VDCC and the ryanodine receptor in the skeletal muscle sarcoplasmic reticulum.
Published: 1997
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37. 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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38. Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum

Author: Diana Xerxes, Bharucha-Goebel, Mariarita, Santi, Livija, Medne, Kristen, Zukosky, Kristin, Zukosky, Jahannaz, Dastgir, Perry B, Shieh, Thomas, Winder, Gihan, Tennekoon, Richard S, Finkel, James J, Dowling, Nicole, Monnier, and Carsten G, Bönnemann
Subjects: Male, Pathology, medicine.medical_specialty, Gene mutation, Biology, Article, medicine, Humans, Abnormalities, Multiple, Myopathy, Central Core, Myopathy, History, Ancient, Arthrogryposis, RYR1, Muscle biopsy, medicine.diagnostic_test, Genetic heterogeneity, Infant, Newborn, Ryanodine Receptor Calcium Release Channel, musculoskeletal system, medicine.disease, Hypotonia, Child, Preschool, Mutation, Female, Neurology (clinical), medicine.symptom, tissues, Central core disease
Abstract: Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 ( RYR1 ) gene–related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients. Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR1 -associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed. Results: Clinical features associated with the severe neonatal presentation of RYR1 -associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype—findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores. Conclusions: This series confirms and expands the clinical and histologic variability associated with severe congenital RYR1 -associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1 -associated myopathy in the appropriate clinical context.
Published: 2013

39. A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies

Author: Nicole Monnier, Leigh B. Waddell, Kathryn N. North, Nigel G. Laing, Mark R. Davis, James J. Dowling, Nigel F. Clarke, Akanchha Kesari, Jaya Punetha, Eric P. Hoffman, Sandra Camelo-Piragua, James W. Teener, and Kimberly Amburgey
Subjects: Proband, Adult, Pathology, medicine.medical_specialty, Weakness, Adolescent, Cardiomyopathy, Biology, medicine.disease_cause, Article, Muscular Diseases, medicine, Humans, Genetic Predisposition to Disease, Myopathy, Genetics (clinical), Mutation, Myosin Heavy Chains, Congenital fiber type disproportion, medicine.disease, Neurology, Pediatrics, Perinatology and Child Health, MYH7, Histopathology, Female, Neurology (clinical), medicine.symptom, Cardiac Myosins
Abstract: MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated.
Published: 2013

40. Congenital myopathy with focal loss of cross-striations revisited

Author: Eleonora Aronica, Heinz Jungbluth, Nicol C. Voermans, Michael Swash, M. de Visser, Nicole Monnier, Joël Lunardi, Amsterdam Neuroscience, Amsterdam Public Health, Neurology, and Pathology
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, Myotonia Congenita, DCN MP - Plasticity and memory, Biopsy, Comorbidity, Biology, Compound heterozygosity, Ocular Motility Disorders, medicine, Humans, Muscle, Skeletal, Pathological, Genetics (clinical), Netherlands, RYR1, Muscle biopsy, medicine.diagnostic_test, External ophthalmoplegia, Eye Diseases, Hereditary, Ryanodine Receptor Calcium Release Channel, Anatomy, medicine.disease, Congenital myopathy, Fibrosis, Pedigree, Neurology, Pediatrics, Perinatology and Child Health, Mutation, Female, Neurology (clinical), Central core disease, Follow-Up Studies
Abstract: Item does not contain fulltext In 1977 Wijngaarden et al. reported a Dutch family with a congenital myopathy characterized by external ophthalmoplegia and a remarkable histological feature, focal loss of cross-striations. A small number of other families with similar clinical and pathological features led to the consideration of this congenital myopathy as a distinct entity. Here we present more than 30years of follow-up from the Dutch family and report recently identified compound heterozygous mutations in the skeletal muscle ryanodine receptor (RYR1) gene, c.10627-2A>G and p.Arg3539His (c.10616G>A). Focal loss of cross-striations on muscle biopsy is another histopathological feature that should raise the possibility of RYR1 involvement.
Published: 2013

41. Exon Skipping as a Therapeutic Strategy Applied to a RyR1 Mutation Causing Severe Core Myopathy

Author: John Rendu, Julie Brocard, Nicole Monnier, France Piétri-Rouxel, Luis Garcia, Joël Lunardi, Julien Fauré, Anne Fourest-Lieuvin, and Isabelle Marty
Subjects: RYR1, Mutation, Biophysics, Skeletal muscle, Biology, musculoskeletal system, medicine.disease_cause, medicine.disease, Molecular biology, Exon skipping, Cell biology, Exon, Calcium imaging, medicine.anatomical_structure, medicine, medicine.symptom, Myopathy, tissues, Central core disease
Abstract: Central Core Disease is a myopathy resulting generally from a mutation in the RYR1 gene, encoding the skeletal muscle calcium release channel RyR1. No treatment is currently available for this disease. We studied a pathological situation in which an affected child harbors two recessive mutations, resulting in a massive reduction in the RyR1 amount. The paternal mutation inducing the inclusion of a new in frame exon in the mRNA of RyR1, resulted in the insertion of additional amino-acids and destabilization of the protein. We hypothesized that inducing the skipping of this exon would be sufficient to restore RyR1 expression and normalization of calcium releases. We developed U7-AON lentiviral vectors to induce exon-skipping on affected primary muscle cells. The efficiency of the exon skipping at the mRNA level, at the protein level and at the functional level using calcium imaging were evaluated. We observed in these affected primary muscle culture a reduction in the inclusion of the additional exon, an increase in the RyR1 protein expression, and a restoration of normal calcium releases. This study is the first demonstration of the potential of exon skipping for the therapy of Central Core Disease, from the molecular to the functional level.
Published: 2013
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42. 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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43. 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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44. Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms

Author: Isabelle Pénisson-Besnier, Susana Quijano-Roy, Norma B. Romero, Julien Ochala, David S. Gokhin, Velia M. Fowler, Nicole Monnier, and Joël Lunardi
Subjects: Adult, Male, medicine.medical_specialty, macromolecular substances, Tropomyosin, medicine.disease_cause, Muscular Diseases, Internal medicine, Myosin, Genetics, medicine, Humans, Myopathy, Child, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Actin, Aged, Mutation, biology, Thiadiazines, Skeletal muscle, General Medicine, Articles, Middle Aged, Actin cytoskeleton, Troponin, Cell biology, Actin Cytoskeleton, Endocrinology, medicine.anatomical_structure, biology.protein, Quinolines, Female, medicine.symptom
Abstract: In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.
Published: 2012

45. Whole-Body muscle MRI in a series of patients with congenital myopathy related to TPM2 gene mutations

Author: Adrien May, Anthony Behin, Robert-Yves Carlier, Pierre G. Carlier, Eugenio Mercuri, Nicole Monnier, Pascale Richard, Valérie Allamand, Mohamed Jarraya, Daniela Avila-Smirnov, Norma B. Romero, Brigitte Estournet, A. Barois, and Susana Quijano-Roy
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Rectus femoris muscle, Tropomyosin, Biology, Gene mutation, TPM2, Young Adult, Nemaline myopathy, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Muscular Diseases, medicine, Humans, Whole Body Imaging, Child, Muscle, Skeletal, Genetics (clinical), Retrospective Studies, Soleus muscle, Arthrogryposis, Anatomy, Middle Aged, medicine.disease, Congenital myopathy, Magnetic Resonance Imaging, Masticatory force, Neurology, Pediatrics, Perinatology and Child Health, Mutation, Female, Neurology (clinical), medicine.symptom
Abstract: Beta-tropomyosin 2 ( TPM2 ) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, ‘cap disease', Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles. The lower leg showed constant soleus muscle involvement, and often also involvement of peroneus, tibialis anterior, and toe flexor muscles. Pelvic and shoulder girdles, and upper limbs muscles were quite spared. Two adult subjects (a patient and a paucisymptomatic parent) had a more diffuse involvement with striking fat infiltration of the rectus femoris muscle. Two children showed variant findings: one presented with masseter involvement associated with severe axial fat infiltration, the second had masticatory and distal leg muscle involvement (soleus and gastrocnemius muscles). Our study suggests that, independently of the clinical and histological presentation, most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. More spread involvement may be observed. This cephalic-distal MRI pattern is not frequent in other known myopathies.
Published: 2012

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

Author: Alain Lacampagne, Antoine Leenhardt, Julie Brocard, Nicole Monnier, Nathalie Roux-Buisson, Marine Cacheux, Julien Fauré, V. Lucet, Pierre F. Ray, Jérémy Fauconnier, Anne Fourest-Lieuvin, Isabelle Marty, Pauline Trémeaux, Isabelle Denjoy, Joël Lunardi, Philippe Mabo, Pascale Guicheney, Philippe Durand, Florence Kyndt, Vincent Probst, Hervé Le Marec, Elodie Santoni, Roux-Buisson, Nathalie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, Service de Réanimation Pédiatrique et Médecine Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de rythmologie pédiatrique, Château des Côtes, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon, AGeing and IMagery (AGIM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie et Génétique Moléculaire, INSERM, Association Française contre les myopathies (AFM), CNRS, Fondation Daniel Ducoin, PHRC, DRC du CHU Grenoble, Société Française de Myologie (SFM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon-Hôpital Michallon, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA)-Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie et maladies vasculaires, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Biochimie et Génétique Moléculaire, Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Biochimie et Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)
Subjects: Male, Muscle Proteins, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, MESH: Protein Isoforms, Endoplasmic Reticulum, Ryanodine receptor 2, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Mutant protein, MESH: Reverse Transcriptase Polymerase Chain Reaction, Chlorocebus aethiops, Missense mutation, Protein Isoforms, Myocytes, Cardiac, MESH: Animals, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Mice, Knockout, 0303 health sciences, Ryanodine receptor, Reverse Transcriptase Polymerase Chain Reaction, MESH: Genetic Predisposition to Disease, General Medicine, Articles, 3. Good health, Pedigree, MESH: COS Cells, MESH: Arrhythmias, Cardiac, MESH: Calcium, COS Cells, cardiovascular system, Female, MESH: Mutation, MESH: Rats, MESH: Pedigree, Nonsense mutation, Blotting, Western, Genes, Recessive, MESH: Carrier Proteins, Biology, Catecholaminergic polymorphic ventricular tachycardia, Sudden death, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Endoplasmic Reticulum, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Blotting, Western, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Family Health, MESH: Humans, Cell Membrane, Arrhythmias, Cardiac, MESH: Death, Sudden, Cardiac, medicine.disease, Molecular biology, MESH: Cercopithecus aethiops, MESH: Male, Rats, Death, Sudden, Cardiac, Triadin, Mutation, Tachycardia, Ventricular, MESH: Family Health, Calcium, MESH: Tachycardia, Ventricular, Carrier Proteins, MESH: Female, MESH: Cell Membrane
Abstract: International audience; Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.
Published: 2012
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47. Mutation Screening of the RYR1 Gene in Malignant Hyperthermia: Detection of a Novel Tyr to Ser Mutation in a Pedigree with Associated Central Cores

Author: Nicole Monnier, Joël Lunardi, J.M.Sandra Healy, I. Krivosic, Bernadette M. Manning, Kathleen A. Quane, Tommie V. McCarthy, Katherine E. Keating, and Renee Krivosic-Horber
Subjects: Male, Genetic Linkage, DNA Mutational Analysis, Molecular Sequence Data, Muscle Proteins, Gene mutation, Biology, Myopathies, Nemaline, medicine.disease_cause, Serine, Genetics, medicine, Humans, Point Mutation, Missense mutation, Genetic Predisposition to Disease, Amino Acid Sequence, Genetic Testing, Gene, Polymorphism, Single-Stranded Conformational, RYR1, Mutation, Base Sequence, Point mutation, Ryanodine Receptor Calcium Release Channel, Single-strand conformation polymorphism, Cardiomyopathy, Hypertrophic, medicine.disease, Pedigree, Genes, Tyrosine, Female, Calcium Channels, Malignant Hyperthermia, Chromosomes, Human, Pair 19, Central core disease
Abstract: The ryanodine receptor gene (RYR1) has been shown to be mutated in a small number of malignant hyperthermia (MH) pedigrees. Missense mutations in this gene have also been identified in two families with central core disease (CCD), a rare myopathy closely associated with MH. In an effort to identify other RYR1 mutations responsible for MH and CCD, we used a SSCP approach to screen the RYR1 gene for mutations in a family exhibiting susceptibility to MH (MHS) where some of the MHS individuals display core regions in their muscle. Sequence analysis of a unique aberrant SSCP has allowed us to identify a point mutation cosegregating with MHS in the described family. The mutation changes a conserved tyrosine residue at position 522 to a serine residue. This mutation is positioned relatively close to five of the six MHS/CCD mutations known to date and provides further evidence that MHS/CCD mutations may cluster in the amino terminal region of the RYR1 protein.
Published: 1994
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48. Using complementary DNA from MyoD-transduced fibroblasts to sequence large muscle genes

Author: Nigel F. Clarke, Leigh B. Waddell, Kathryn N. North, Sandra T. Cooper, and Nicole Monnier
Subjects: Messenger RNA, DNA, Complementary, Physiology, Nonsense mutation, Nonsense-mediated decay, Biology, Fibroblasts, MyoD, Molecular biology, Polymerase Chain Reaction, Cellular and Molecular Neuroscience, chemistry.chemical_compound, genomic DNA, chemistry, Physiology (medical), Complementary DNA, Humans, Neurology (clinical), RNA, Messenger, Muscle, Skeletal, Gene, DNA
Abstract: Large muscle genes are often sequenced using complementary DNA (cDNA) made from muscle messenger RNA (mRNA) to reduce the cost and workload associated with sequencing from genomic DNA. Two potential barriers are the availability of a frozen muscle biopsy, and difficulties in detecting nonsense mutations due to nonsense-mediated mRNA decay (NMD). We present patient examples showing that use of MyoD-transduced fibroblasts as a source of muscle-specific mRNA overcomes these potential difficulties in sequencing large muscle-related genes.
Published: 2011

49. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion

Author: S. Lillis, Kate Bushby, Joël Lunardi, Volker Straub, Leigh B. Waddell, Isabelle Marty, Nigel F. Clarke, Sandra T. Cooper, Nicole Monnier, Michela Guglieri, Andrew J. Kornberg, Mary D. King, Robert L. Smith, Francesco Muntoni, Margaret Perry, Kathryn N. North, and Michael A. Farrell
Subjects: Male, Pathology, medicine.medical_specialty, Heterozygote, Adolescent, Blotting, Western, DNA Mutational Analysis, Genes, Recessive, Biology, medicine.disease_cause, Compound heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), 030304 developmental biology, RYR1, Family Health, 0303 health sciences, Mutation, Infant, Heterozygote advantage, Fiber size, Ryanodine Receptor Calcium Release Channel, Congenital fiber type disproportion, musculoskeletal system, medicine.disease, Congenital myopathy, Muscle Fibers, Slow-Twitch, Child, Preschool, Female, Abnormality, tissues, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.
Published: 2010

50. De novo RYR1 heterozygous mutation (I4898T) causing lethal core-rod myopathy in twins

Author: Guy Brochier, Michel Fardeau, Emmanuelle Lacène, Kristl G. Claeys, Norma B. Romero, Nicole Monnier, Isabelle Husson, Aurelio Hernández-Laín, Caroline Farnoux, Maud Beuvin, Joël Lunardi, L Manere, Thomas Voit, Mait Viou, 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), Servicio Anatomia Patológica, Neuropatologia, Hospital 12 Octubre, Services de Neuropédiatrie et Réanimation Infantile, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, 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-Centre de Référence des Maladies Neuro-Musculaires-CHU Grenoble-Centre de Référence des Maladies Neuro-Musculaires, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM, Association Française contre les Myopathies, Association Institut de Myologie, CNRS, France and the Fundación para la Investigación Biomédica, Hospital 12 Octubre, Madrid, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Roux-Buisson, Nathalie
Subjects: Male, MESH: Fatal Outcome, Pathology, DNA Mutational Analysis, Twins, Muscle Proteins, medicine.disease_cause, Myopathies, Nemaline, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, Fatal Outcome, Myopathy, Central Core, MESH: DNA Mutational Analysis, Genetics (clinical), Genetics, Arthrogryposis, MESH: Muscle, Skeletal, 0303 health sciences, Mutation, MESH: Infant, Newborn, General Medicine, MESH: Infant, MESH: Myopathies, Nemaline, Hypotonia, 3. Good health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, medicine.medical_specialty, MESH: Mutation, MESH: Myopathy, Central Core, MESH: Microscopy, Electron, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Actins, MESH: Muscle Proteins, 03 medical and health sciences, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Myopathy, Muscle, Skeletal, Actin, 030304 developmental biology, RYR1, MESH: Humans, MESH: Twins, Infant, Newborn, Infant, Ryanodine Receptor Calcium Release Channel, medicine.disease, Congenital myopathy, MESH: Male, Actins, Microscopy, Electron, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030217 neurology & neurosurgery, Central core disease
Abstract: International audience; "Core-rod myopathy" is a rare congenital myopathy characterized by the presence of "cores" and "rods" in distinct locations in the same or different muscle fibres. This association is linked currently to mutations in RYR1, NEB and ACTA1 genes. We report identical twins who presented with polyhydramnios and loss of fetal motility during pregnancy; hypotonia, arthrogryposis and swallowing impairment at birth; need of immediate respiratory support and death at 27 and 50 days of life. Muscle biopsies, performed at 27 days of life in twin 1 and at 49 days in twin 2, showed the presence of separate cores and rods in the muscle fibres, both at light and electron microscopy. The molecular analysis showed a heterozygous de novo mutation (Ile4898Thr) of the RYR1 gene. The molecular study of ACTA1, TMP2 and TMP3 genes did not show abnormalities. This is the first report of a lethal form of congenital "core-rod myopathy". The mutation Ile4898Thr has been previously described in central core disease but not in core-rod myopathy. The report enlarges the phenotypic spectrum of "core-rod myopathy" and highlights the morphological variability associated to special RYR1 mutations.
Published: 2009
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