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1. Human genetic structure in Northwest France provides new insights into West European historical demography

Author: Isabel Alves, Joanna Giemza, Michael G. B. Blum, Carolina Bernhardsson, Stéphanie Chatel, Matilde Karakachoff, Aude Saint Pierre, Anthony F. Herzig, Robert Olaso, Martial Monteil, Véronique Gallien, Elodie Cabot, Emma Svensson, Delphine Bacq, Estelle Baron, Charlotte Berthelier, Céline Besse, Hélène Blanché, Ozvan Bocher, Anne Boland, Stéphanie Bonnaud, Eric Charpentier, Claire Dandine-Roulland, Claude Férec, Christine Fruchet, Simon Lecointe, Edith Le Floch, Thomas E. Ludwig, Gaëlle Marenne, Vincent Meyer, Elisabeth Quellery, Fernando Racimo, Karen Rouault, Florian Sandron, Jean-Jacques Schott, Lourdes Velo-Suarez, Jade Violleau, Eske Willerslev, Yves Coativy, Mael Jézéquel, Daniel Le Bris, Clément Nicolas, Yvan Pailler, Marcel Goldberg, Marie Zins, Hervé Le Marec, Mattias Jakobsson, Pierre Darlu, Emmanuelle Génin, Jean-François Deleuze, Richard Redon, and Christian Dina
Subjects: Science
Abstract: Abstract The demographical history of France remains largely understudied despite its central role toward understanding modern population structure across Western Europe. Here, by exploring publicly available Europe-wide genotype datasets together with the genomes of 3234 present-day and six newly sequenced medieval individuals from Northern France, we found extensive fine-scale population structure across Brittany and the downstream Loire basin and increased population differentiation between the northern and southern sides of the river Loire, associated with higher proportions of steppe vs. Neolithic-related ancestry. We also found increased allele sharing between individuals from Western Brittany and those associated with the Bell Beaker complex. Our results emphasise the need for investigating local populations to better understand the distribution of rare (putatively deleterious) variants across space and the importance of common genetic legacy in understanding the sharing of disease-related alleles between Brittany and people from western Britain and Ireland.
Published: 2024
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2. Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes

Author: Nobue Yagihara, Hiroshi Watanabe, Phil Barnett, Laetitia Duboscq‐Bidot, Atack C. Thomas, Ping Yang, Seiko Ohno, Kanae Hasegawa, Ryozo Kuwano, Stéphanie Chatel, Richard Redon, Jean‐Jacques Schott, Vincent Probst, Tamara T. Koopmann, Connie R. Bezzina, Arthur A. M. Wilde, Yukiko Nakano, Takeshi Aiba, Yoshihiro Miyamoto, Shiro Kamakura, Dawood Darbar, Brian S. Donahue, Daichi Shigemizu, Toshihiro Tanaka, Tatsuhiko Tsunoda, Masayoshi Suda, Akinori Sato, Tohru Minamino, Naoto Endo, Wataru Shimizu, Minoru Horie, Dan M. Roden, and Naomasa Makita
Subjects: arrhythmias, genetics, ion channels, sodium channels, transcription, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Mutations in the coding sequence of SCN5A, which encodes the cardiac Na+ channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. Methods and Results We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild‐type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity. Conclusions Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
Published: 2016
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3. Dysfunction of the Voltage‐Gated K+ Channel β2 Subunit in a Familial Case of Brugada Syndrome

Author: Vincent Portero, Solena Le Scouarnec, Zeineb Es‐Salah‐Lamoureux, Sophie Burel, Jean‐Baptiste Gourraud, Stéphanie Bonnaud, Pierre Lindenbaum, Floriane Simonet, Jade Violleau, Estelle Baron, Eléonore Moreau, Carol Scott, Stéphanie Chatel, Gildas Loussouarn, Thomas O'Hara, Philippe Mabo, Christian Dina, Hervé Le Marec, Jean‐Jacques Schott, Vincent Probst, Isabelle Baró, Céline Marionneau, Flavien Charpentier, and Richard Redon
Subjects: Brugada syndrome, cardiac arrhythmia, clinical electrophysiology, genetics, KCNAB2/Kvβ2, potassium ion channels, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundThe Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. Methods and ResultsWe combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage‐gated K+ channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K+ channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in COS‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2. ConclusionsAltogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
Published: 2016
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4. Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block

Author: Ninda Syam, Stéphanie Chatel, Lijo Cherian Ozhathil, Valentin Sottas, Jean‐Sébastien Rougier, Alban Baruteau, Estelle Baron, Mohamed‐Yassine Amarouch, Xavier Daumy, Vincent Probst, Jean‐Jacques Schott, and Hugues Abriel
Subjects: atrioventricular block, mutations, temperature‐dependent rescue, transient receptor potential melastatin member 4, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundTransient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4‐dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block. Methods and ResultsNinety‐one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole‐cell patch‐clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMOylation of TRPM4 may cause a gain of function; however, we did not find any evidence that supports SUMOylation as being directly involved for the gain‐of‐function variant. ConclusionsThis study underpins the role of TRPM4 in the cardiac conduction system. The loss‐of‐function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding‐dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.
Published: 2016
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5. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel.

Author: Hui Liu, Stéphanie Chatel, Christophe Simard, Ninda Syam, Laurent Salle, Vincent Probst, Julie Morel, Gilles Millat, Michel Lopez, Hugues Abriel, Jean-Jacques Schott, Romain Guinamard, and Patrice Bouvagnet
Subjects: Medicine, Science
Abstract: Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ~14'000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.
Published: 2013
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6. Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility (Nature Genetics, (2022), 54, 3, (232-239), 10.1038/s41588-021-01007-6)

Author: Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Julien Barc, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
Abstract: In the version of this article initially published, Federico Manevy’s name appeared with a middle initial in error. The name has been corrected in the HTML and PDF versions of the article.
Published: 2022

7. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author: Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, Connie R. Bezzina, Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George Jr., Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon &, and Connie R. Bezzina
Abstract: Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
Published: 2022

8. Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Author: Romain Bourcier, Solena Le Scouarnec, Stéphanie Bonnaud, Matilde Karakachoff, Emmanuelle Bourcereau, Sandrine Heurtebise-Chrétien, Céline Menguy, Christian Dina, Floriane Simonet, Alexis Moles, Cédric Lenoble, Pierre Lindenbaum, Stéphanie Chatel, Bertrand Isidor, Emmanuelle Génin, Jean-François Deleuze, Jean-Jacques Schott, Hervé Le Marec, Gervaise Loirand, Hubert Desal, Richard Redon, Benjamin Daumas-Duport, Jérôme Connault, Pierre Lebranchu, Thierry Le Tourneau, Marie Pierre Viarouge, Chrisanthi Papagiannaki, Michel Piotin, Hocine Redjem, Mikael Mazighi, Jean Philippe Desilles, Olivier Naggara, Denis Trystram, Myriam Edjlali-Goujon, Christine Rodriguez, Waghi Ben Hassen, Suzanna Saleme, Charbel Mounayer, Olivier Levrier, Pierre Aguettaz, Xavier Combaz, Anne Pasco, Emeline Berthier, Marc Bintner, Marc Molho, Pascale Gauthier, Cyril Chivot, Vincent Costalat, Cyril Darganzil, Alain Bonafé, Anne Christine Januel, Caterina Michelozzi, Christophe Cognard, Fabrice Bonneville, Philippe Tall, Jean Darcourt, Alessandra Biondi, Cristina Iosif, Elisa Pomero, Jean Christophe Ferre, Jean Yves Gauvrit, François Eugene, Hélène Raoult, Jean Christophe Gentric, Julien Ognard, René Anxionnat, Serge Bracard, Anne Laure Derelle, Romain Tonnelet, Laurent Spelle, Léon Ikka, Robert Fahed, Aymeric Rouchaud, Augustin Ozanne, Jildaz Caroff, Nidal Ben Achour, Jacques Moret, Emmanuel Chabert, Jérôme Berge, Gaultier Marnat, Xavier Barreau, Florent Gariel, Frédéric Clarencon, Mohammed Aggour, Frédéric Ricolfi, Adrien Chavent, Pierre Thouant, Pablo Lebidinsky, Brivael Lemogne, Denis Herbreteau, Richard Bibi, Laurent Pierot, Sébastien Soize, Marc Antoine Labeyrie, Christophe Vandendries, Emmanuel Houdart, Appoline Kazemi, Xavier Leclerc, Jean Pierre Pruvo, Sophie Gallas, Stéphane Velasco, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Sciences du Numérique de Nantes (LS2N), IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neuroradiologie [Paris], Hôpital Sainte-Anne, Service de Neuroradiologie interventionnelle [CHU Limoges], CHU Limoges, BIO-INGENIERIE (XLIM-BIO-INGENIERIE), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Microbiologie Environnement Digestif Santé (MEDIS), INRA Clermont-Ferrand-Theix-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuroradiologie Diagnostique et Thérapeutique [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Radiologie [CHU de Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], CHU Pontchaillou [Rennes], Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Lorraine (UL), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Department of Neuroradiology, Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre, CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Registre Dijonnais des Accidents Vasculaires Cérébraux (AVC) - Dijon Stroke Registry, Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Reims Champagne-Ardenne (URCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Services de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR-15-CE17-0008,I-CAN,Anévrismes intracraniens : des formes familiales aux méchanismes physiopathologiques(2015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service Neuroradiologie Diagnostique et Thérapeutique [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Neurosciences de Montpellier (INM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université de Rennes (UR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Subarachnoid hemorrhage, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], Gastroenterology, Article, 03 medical and health sciences, Exon, Open Reading Frames, 0302 clinical medicine, Aneurysm, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Internal medicine, Genetics, medicine, Humans, Family, Genetic Predisposition to Disease, Angiopoietin-Like Protein 6, Allele, Index case, Gene, Genetics (clinical), Exome sequencing, Cells, Cultured, business.industry, Intracranial Aneurysm, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Blood pressure, Angiopoietin-like Proteins, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Mutation, Female, business, 030217 neurology & neurosurgery
Abstract: International audience; Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)—which encodes a circulating pro-angiogenic factor mainly secreted from the liver—shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
Published: 2018

9. Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project

Author: Gervaise Loirand, Pierre Lebranchu, Benjamin Daumas-Duport, Alban Gaignard, Solène Jouan, Vincent Roualdes, Bertrand Isidor, Tanguy Riem, Hubert Desal, Emmanuelle Bourcereau, Richard Redon, Stéphanie Chatel, Thierry Le Tourneau, Benoit Guillon, Mathieu Sevin-Allouet, Jérôme Connault, Ican Investigators, Romain Bourcier, Hervé Le Marec, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Physiologie de la Perception et de l'Action (LPPA), Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Computational biology, Diagnostic tools, Imaging data, Pathophysiology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Familial, Risk Factors, Genetic variation, Genetics, Medicine, Humans, Genetic risk, Mechanism (biology), Potential risk, business.industry, Intracranial Aneurysm, Aneurysm, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic marker, Surgery, Identification (biology), Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA.OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture.METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data.EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets.DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.
Published: 2017

10. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author: Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics
Subjects: Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Published: 2014

11. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author: Jade Violleau, Stefan Kääb, Susan Bartkowiak, Richard Redon, Antoine Leenhardt, Hanno L. Tan, Jean-Baptiste Gourraud, Peter Weeke, Rachel Bastiaenen, Rianne Wolswinkel, Federica Dagradi, Vincent M. Christoffels, Jacob Tfelt-Hansen, Jean-Jacques Schott, Hervé Le Marec, Manfred Gessler, Françoise Gros, Pascale Guicheney, Julien Barc, Arthur A.M. Wilde, Simon Lecointe, Akihiko Nogami, Tohru Minamino, Sven Zumhagen, Margherita Torchio, Elijah R. Behr, Rainer Schimpf, Carol Ann Remme, Florence Kyndt, Lia Crotti, Yuka Mizusawa, Morten S. Olesen, Vincent Probst, Naoto Endo, Naomasa Makita, Eric Charpentier, Philippe Froguel, Arie O. Verkerk, Minoru Horie, Takeshi Aiba, Christian Dina, Peter J. Schwartz, Kanae Hasegawa, Floriane Simonet, Véronique Fressart, Seiko Ohno, Cornelia Wiese, Eric Schulze-Bahr, Stéphane Bézieau, Hiroshi Watanabe, Vincent Portero, Wataru Shimizu, Beverley Balkau, Martin Borggrefe, Britt M. Beckmann, Charles Antzelevitch, Bas J. Boukens, Dan M. Roden, Pierre Lindenbaum, Aurore Despres, David Weber, Olivier Lantieri, Connie R. Bezzina, Stéphanie Chatel, Ruben Coronel, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Medical Biology, Other departments, ARD - Amsterdam Reproduction and Development, Bezzina, C, Barc, J, Mizusawa, Y, Remme, C, Gourraud, J, Simonet, F, Verkerk, A, Schwartz, P, Crotti, L, Dagradi, F, Guicheney, P, Fressart, V, Leenhardt, A, Antzelevitch, C, Bartkowiak, S, Borggrefe, M, Schimpf, R, Schulze-Bahr, E, Zumhagen, S, Behr, E, Bastiaenen, R, Tfelt-Hansen, J, Olesen, M, Kääb, S, Beckmann, B, Weeke, P, Watanabe, H, Endo, N, Minamino, T, Horie, M, Ohno, S, Hasegawa, K, Makita, N, Nogami, A, Shimizu, W, Aiba, T, Froguel, P, Balkau, B, Lantieri, O, Torchio, M, Wiese, C, Weber, D, Wolswinkel, R, Coronel, R, Boukens, B, Bézieau, S, Charpentier, E, Chatel, S, Despres, A, Gros, F, Kyndt, F, Lecointe, S, Lindenbaum, P, Portero, V, Violleau, J, Gessler, M, Tan, H, Roden, D, Christoffels, V, Le Marec, H, Wilde, A, Probst, V, Schott, J, Dina, C, and Redon, R
Subjects: Male, Qrs Duration, Bioinformatics, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, Genome-Wide Association, Mice, Atrial Gene-Expression, Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Brugada Syndrome, Brugada syndrome, Mice, Knockout, St-Segment Elevation, SECS-S/01 - STATISTICA, cardiovascular system, Cardiology, Chromosomes, Human, Pair 6, Female, Chromosomes, Human, Pair 3, medicine.medical_specialty, Bundle-Branch Block, BIO/18 - GENETICA, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, NAV1.8 Voltage-Gated Sodium Channel, Internal medicine, Genetic variation, Cardiac conduction, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, cardiovascular diseases, HEY2, Alleles, Heart-Rate, Genetic Variation, Cardiac arrhythmia, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Qt Interval Duration, Repressor Proteins, Ventricular-Fibrillation, Pr Interval, Death, Sudden, Cardiac, Case-Control Studies, Conduction System, Genome-Wide Association Study, Rare disease
Abstract: Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
Published: 2013

12. Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome

Author: Jean-Luc Pasquié, Alexandre Duparc, P. Jaïs, A. Rollin, Marie Sadron, L. Jesel, Stéphanie Chatel, Pierre Mondoly, Marc Delay, C. Cardin, F. Raczka, Frederic Sacher, Jean-Marc Davy, Arnaud Denis, M. Hocini, Nicolas Derval, M. Haissaguerre, Jean-Baptiste Gourraud, Philippe Maury, and Vincent Probst
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Sudden death, Asymptomatic, Sudden cardiac death, Electrocardiography, Young Adult, Physiology (medical), Internal medicine, Prevalence, medicine, Humans, Electrodes, Aged, Brugada Syndrome, Retrospective Studies, Brugada syndrome, Aged, 80 and over, ST depression, medicine.diagnostic_test, business.industry, ST elevation, Atrial fibrillation, Middle Aged, medicine.disease, Survival Rate, Death, Sudden, Cardiac, Cardiology, Female, France, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Despite isolated reports of Brugada syndrome (BrS) in the inferior or lateral leads, the prevalence and prognostic value of ST elevation in the peripheral electrocardiographic (ECG) leads in patients with BrS remain poorly known.To study the prevalence, characteristics, and prognostic value of type 1 ST elevation and ST depression in the peripheral ECG leads in a large cohort of patients with BrS.ECGs from 323 patients with BrS (age 47 ± 13 years; 257 men) with spontaneous (n = 141) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of 48 ± 34 months.Thirty (9%) patients presented with type 1 ST elevation in at least 1 peripheral lead (22 patients in the aVR leads, 2 in the inferior leads, 5 in both aVR and inferior leads, and 1 in the aVR and VL leads). Patients with type 1 ST elevation in the peripheral leads more often had mutations in the SCN5A gene, were more often inducible, had slower heart rate, and higher J-wave amplitude in the right precordial leads. Twenty-seven percent (8 of 30) of the patients with type 1 ST elevation in the peripheral leads experimented sudden death/appropriate implantable cardioverter-defibrillator therapy, whereas it occurred in only 6% (18 of 293) of other patients (P.0001). In multivariate analysis, type 1 ECG in the peripheral leads was independently associated with malignant arrhythmic events (odds ratio 4.58; 95% confidence interval 1.7-12.32; P = .0025).Type 1 ST elevation in the peripheral ECG leads can be seen in 10% of the patients with BrS and is an independent predictor for a malignant arrhythmic event.
Published: 2013

13. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

Author: Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B. Haack, Salim Khiati, Anne-Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A. Aleck, Lorenzo D. Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N’Guyen, José Antonio Mora-Lorca, Birgit Assmann, Stine Christ, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Antonio Miranda-Vizuete, Georg F. Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau, Emmanuelle Génin, Dominique Campion, Jean-François Dartigues, Jean-François Deleuze, Jean-Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier Quenez, Christian Dina, Céline Bellenguez, Camille Charbonnier -Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gaël Nicolas, Karen Rouault, Delphine Bacq, Anne Boland, Doris Lechner, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Médicale Pédiatrique, Centre hospitalier universitaire de Nantes (CHU Nantes), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), and Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health
Subjects: 0301 basic medicine, Male, Microcephaly, Movement disorders, [SDV]Life Sciences [q-bio], Ubiquitin-Activating Enzymes, Endoplasmic Reticulum, Synaptic Transmission, Exome, Genetics(clinical), Age of Onset, Child, Zebrafish, Genetics (clinical), Caenorhabditis elegans, Genetics, Brain Diseases, Brain Mapping, Movement Disorders, biology, Magnetic Resonance Imaging, Cholinergic Neurons, 3. Good health, Child, Preschool, Female, medicine.symptom, Encephalopathy, Genes, Recessive, 03 medical and health sciences, Intellectual Disability, Report, medicine, Gene silencing, Animals, Humans, Caenorhabditis elegans Proteins, Gene, Ubiquitins, Alleles, Epilepsy, Ubiquitin, Endoplasmic reticulum, Proteins, Fibroblasts, Zebrafish Proteins, biology.organism_classification, medicine.disease, 030104 developmental biology, Mutation
Abstract: International audience; Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.
Published: 2016

14. Dysfunction of the Voltage‐Gated K + Channel β2 Subunit in a Familial Case of Brugada Syndrome

Author: Gildas Loussouarn, Vincent Probst, Thomas O'Hara, Christian Dina, Carol Scott, Eléonore Moreau, Solena Le Scouarnec, Stéphanie Chatel, Stéphanie Bonnaud, Hervé Le Marec, Sophie Burel, Flavien Charpentier, Jade Violleau, Isabelle Baró, Estelle Baron, Pierre Lindenbaum, Vincent Portero, Jean-Jacques Schott, Floriane Simonet, Céline Marionneau, Philippe Mabo, Zeineb Es‐Salah‐Lamoureux, Jean-Baptiste Gourraud, Richard Redon, Jonchère, Laurent, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), The Wellcome Trust Sanger Institute [Cambridge], CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), 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], Leducq Foundation [CVD-05], Fondation pour la Recherche Medicale [DEQ20140329545], Inserm, French Regional Council of Pays-de-la-Loire, Fondation Lefoulon-Delalande, Fondation pour la Recherche Medicale, Fondation Genavie, Wellcome Trust [WT098051], European Commission [NavEx-256397], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Arrhythmias, 030204 cardiovascular system & hematology, whole exome sequencing, NAV1.5 Voltage-Gated Sodium Channel, Electrocardiography, 0302 clinical medicine, Genotype, Missense mutation, Arrhythmia and Electrophysiology, genetics, Exome sequencing, risk, Original Research, Brugada syndrome, Genetics, maps, clinical electrophysiology, potassium ion channels, potassium channels, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pedigree, 3. Good health, Electrophysiology, modulation, Shal Potassium Channels, Potassium Channels, Voltage-Gated, Gain of Function Mutation, Cardiology, Female, abnormalities, Cardiology and Cardiovascular Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, gene prioritization, j-wave syndromes, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, Sudden death, sudden cardiac death, cardiac arrhythmia, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetic linkage, Internal medicine, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Gene, disease, business.industry, KCNAB2/Kvβ2, mutations, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Shaker Superfamily of Potassium Channels, business
Abstract: Background The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN 5A , the molecular mechanisms underlying this condition are still largely unknown. Methods and Results We combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN 5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB 2 , which encodes the voltage‐gated K + channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K + channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB 2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB 2 variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in COS ‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2. Conclusions Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
Published: 2016

15. Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block

Author: Hugues Abriel, Valentin Sottas, Vincent Probst, Jean-Sébastien Rougier, Stéphanie Chatel, Alban Baruteau, Mohamed Yassine Amarouch, Ninda Syam, Lijo Cherian Ozhathil, Estelle Baron, Jean-Jacques Schott, Xavier Daumy, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Clinical Research, and University of Bern
Subjects: Male, 0301 basic medicine, Pacemaker, Artificial, Protein Folding, Candidate gene, Patch-Clamp Techniques, [SDV]Life Sciences [q-bio], SUMO protein, Arrhythmias, Transient receptor potential channel, temperature‐dependent rescue, transient receptor potential melastatin member 4, Arrhythmia and Electrophysiology, 610 Medicine & health, Child, Atrioventricular Block, Original Research, Brugada syndrome, Reverse Transcriptase Polymerase Chain Reaction, Cardiac Pacing, Artificial, Temperature, Cell biology, Electrophysiology, Protein Transport, Child, Preschool, Female, Cardiology and Cardiovascular Medicine, temperature-dependent rescue, medicine.medical_specialty, TRPM Cation Channels, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Internal medicine, Cardiac conduction, medicine, Humans, Proteostasis Deficiencies, Loss function, business.industry, Cell Membrane, HEK 293 cells, Infant, Newborn, Genetic Variation, Infant, medicine.disease, mutations, HEK293 Cells, 030104 developmental biology, Endocrinology, business, Atrioventricular block
Abstract: Background Transient receptor potential melastatin member 4 ( TRPM 4) is a nonselective cation channel. TRPM 4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM 4‐dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM 4 genetic variants found in patients with congenital or childhood atrioventricular block. Methods and Results Ninety‐one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM 4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK 293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole‐cell patch‐clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMO ylation of TRPM 4 may cause a gain of function; however, we did not find any evidence that supports SUMO ylation as being directly involved for the gain‐of‐function variant. Conclusions This study underpins the role of TRPM 4 in the cardiac conduction system. The loss‐of‐function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding‐dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.
Published: 2016

16. Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes

Author: Ping Yang, Stéphanie Chatel, Laëtitia Duboscq-Bidot, Connie R. Bezzina, Vincent Probst, Tohru Minamino, Tamara T. Koopmann, Nobue Yagihara, Wataru Shimizu, Akinori Sato, Dawood Darbar, Toshihiro Tanaka, Ryozo Kuwano, Kanae Hasegawa, Richard Redon, Jean-Jacques Schott, Phil Barnett, Naomasa Makita, Yoshihiro Miyamoto, Hiroshi Watanabe, Arthur A.M. Wilde, Takeshi Aiba, Masayoshi Suda, Tatsuhiko Tsunoda, Yukiko Nakano, Atack C. Thomas, Naoto Endo, Daichi Shigemizu, Minoru Horie, Dan M. Roden, Brian S. Donahue, Shiro Kamakura, Seiko Ohno, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Amsterdam Cardiovascular Sciences, Medical Biology, Other departments, and Cardiology
Subjects: Male, 0301 basic medicine, lcsh:Diseases of the circulatory (Cardiovascular) system, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, NAV1.5 Voltage-Gated Sodium Channel, 0302 clinical medicine, Cardiac Conduction System Disease, Transcription (biology), Atrial Fibrillation, Medicine, Coding region, Arrhythmia and Electrophysiology, genetics, Child, Promoter Regions, Genetic, sodium channels, Original Research, Brugada Syndrome, Brugada syndrome, Aged, 80 and over, Sick Sinus Syndrome, Genetics, ion channels, Atrial fibrillation, Middle Aged, Phenotype, Regulatory sequence, Ventricular Fibrillation, cardiovascular system, Female, transcription, Cardiology and Cardiovascular Medicine, arrhythmias, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Young Adult, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Transcription factor, Aged, business.industry, Genetic Variation, Arrhythmias, Cardiac, Promoter, Ion Channels/Membrane Transport, medicine.disease, 030104 developmental biology, Endocrinology, lcsh:RC666-701, Mutation, business, Chromatin immunoprecipitation
Abstract: Background Mutations in the coding sequence of SCN 5A , which encodes the cardiac Na + channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN 5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN 5A also modulate the risk of arrhythmias. Methods and Results We resequenced the core promoter region of SCN 5A and the regulatory regions of SCN 5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN 5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild‐type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity. Conclusions Variants in the core promoter region and the transcription regulatory region of SCN 5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN 5A transcription levels modulate susceptibility to arrhythmias.
Published: 2016

17. First steps towards an advanced simulation of composites manufacturing by automated tape placement

Author: Stéphanie Chatel, Brice Bognet, Adrien Leygue, Francisco Chinesta, Anais Barasinski, S. Maison-Le-Poec, Ch. Ghnatios, Arnaud Poitou, Felipe Bordeu, Fabien Poulhaon, Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), and EADS IW
Subjects: PGD, Model order reduction, Engineering, Computer simulation, business.industry, Manufacturing process, Computational intelligence, 02 engineering and technology, 021001 nanoscience & nanotechnology, composites, Manufacturing engineering, Modeling and simulation, 020303 mechanical engineering & transports, automated tape placement, 0203 mechanical engineering, model order reduction, [SPI.MECA.STRU]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Structural mechanics [physics.class-ph], numerical simulation, General Materials Science, Composite material, 0210 nano-technology, business, Proper generalized decomposition
Abstract: International audience; Composite materials and their related manufacturing processes involve many modeling and simulation issues, mainly related to their multi-physics and multi-scale nature, to the strong couplings and the complex geometries. In our former works we developed a new paradigm for addressing the solution of such complex models, the so-called Proper Generalized Decomposition based model order reduction. In this work we are summarizing the most outstanding capabilities of such methodology and then all these capabilities will be put together for addressing efficiently the simulation of a challenging composites manufacturing process, the automated tape placement.
Published: 2012

18. Increased Tpeak-Tend interval is highly and independently related to arrhythmic events in Brugada syndrome

Author: Marie Sadron, Vanina Bongard, Jean-Baptiste Gourraud, Stéphanie Chatel, Nicolas Derval, Pierre Mondoly, Franck Raczka, Arnaud Denis, Philippe Maury, Didier Carrié, Michel Haïssaguerre, Jean-Marc Davy, Anne Rollin, Mélèze Hocini, Christelle Cardin, Jean-Luc Pasquié, Alexandre Duparc, Michel Galinier, Laurence Jesel, Frederic Sacher, Vincent Probst, Pierre Jaïs, CHU Toulouse [Toulouse], IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de Rangueil, Service de cardiologie [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Hôpital Haut-Lévêque, and Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux]
Subjects: Adult, Male, QT interval, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Asymptomatic, Sudden death, Risk Assessment, Electrocardiography, Predictive Value of Tests, Physiology (medical), Internal medicine, medicine, Repolarization, Humans, Brugada syndrome, cardiovascular diseases, Retrospective Studies, business.industry, Odds ratio, Middle Aged, Implantable cardioverter-defibrillator, medicine.disease, Confidence interval, Defibrillators, Implantable, Transmural dispersion of repolarization, ROC Curve, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Risk stratification in Brugada syndrome (BS) remains controversial. The time interval between the peak and the end of the T wave (Tpe interval), a marker of transmural dispersion of repolarization, has been linked to malignant ventricular arrhythmias in various settings but leads to discordant results in BS.We study the correlation of the Tpe interval with arrhythmic events in a large cohort of patients with BS.A total of 325 consecutive patients with BS (mean age 47±13 years, 259 men-80%) with spontaneous (n=143, 44%) or drug-induced (n=182, 56%) type 1 electrocardiogram were retrospectively included. 235 were asymptomatic (70%), 80 presented with unexplained syncope (22%), and 10 presented with sudden death (SD) or appropriate implantable cardioverter-defibrillator therapy (AT) (8%) at diagnosis or over a mean follow-up of 48 ± 34 months. The Tpe interval was calculated as the difference between the QT interval and the QT peak interval as measured in each of the precordial leads.The Tpe interval from lead V1 to lead V4, maximum value of the Tpe interval (max Tpe), and Tpe dispersion in all precordial leads were significantly higher in patients with SD/AT or in patients with syncope than in asymptomatic patients (P.001). A max Tpe of ≥100 ms was present in 47 of 226 asymptomatic patients (21%), in 48 of 73 patients with syncope (66%), and in 22 of 26 patients with SD/AT (85%) (P.0001). In multivariate analysis, a max Tpe of ≥100 ms was independently related to arrhythmic events (odds ratio 9.61; 95% confidence interval 3.13-29.41; P.0001).The Tpe interval in the precordial leads is highly related to malignant ventricular arrhythmias in this large cohort of patients with BS. This simple electrocardiographic parameter could be used to refine risk stratification.
Published: 2015

19. Material characterization and residual stresses simulation during the manufacturing process of epoxy matrix composites

Author: Didier Delaunay, Arnaud Poitou, Frédéric Jacquemin, N. Boyard, Stéphanie Chatel, and Y. Abou Msallem
Subjects: Materials science, Epoxy, Thermal expansion, Finite element method, Characterization (materials science), Mechanics of Materials, Residual stress, visual_art, Ceramics and Composites, visual_art.visual_art_medium, Composite material, Material properties, Glass transition, Shrinkage
Abstract: A thermal, rheological and mechanical material characterization of an aeronautic epoxy resin from commercial prepreg is reported in this article. The kinetic of the crosslinking reaction of the resin is characterized and modeled. The specific heat, the glass transition temperature, the thermal expansion coefficients, the chemical shrinkage coefficients and the thermo-mechanical properties have been investigated as a function of temperature and degree of cure. Dynamic mechanical measurements are used to determine the gel point. Finally, the residual stresses developed during the curing process are calculated using a finite element simulation, taking into account the material properties evolutions according to proposed models. The results highlight the importance of the characterization accuracy and the associated models.
Published: 2010

20. Experimental device for the preforming step of the RTM process

Author: Stéphanie Chatel, Samir Allaoui, and Damien Soulat
Subjects: Shear (sheet metal), Materials science, Buckling, business.industry, Woven fabric, Process (computing), Forming processes, General Materials Science, Development (differential geometry), Structural engineering, Interlock, business, Blank
Abstract: This paper concerns the development of an experimental device which is able to form very complex double curved geometry. Objectives are to analyze the evolution of the woven preform during the forming process. This device contains one mechanical module containing the classical tools in forming process, (punch, blank holder, and open-die), and one optical module to measure the 3D-deformed shape and the distribution of local deformations, like shear angles of the woven reinforcement during all the process. Experimental results are obtained with an interlock carbon woven fabric, used in aeronautical applications. Wrinkling and buckling will be analyzed at the global scale of the piece. The evolution of the shear angle will be presented at local scale (on face, or edges of the geometry).
Published: 2009

21. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel

Author: Michel Haïssaguerre, Yoram Rudy, Rukshen Weerasooriya, Gildas Loussouarn, Frederic Sacher, Joseph C. Koster, Ruedige Liersch M.D., Vincent Probst, Arthur A.M. Wilde, Jean-Jacques Schott, Eric Schulze-Bahr, Marc Horlitz, Stéphanie Chatel, Stefan Kääb, Hervé Le Marec, ACS - Amsterdam Cardiovascular Sciences, and Cardiology
Subjects: medicine.medical_specialty, Potassium Channels, Adolescent, Benign early repolarization, Amiodarone, Polymorphism, Single Nucleotide, Sudden death, Sudden cardiac death, Electrocardiography, KATP Channels, Physiology (medical), Internal medicine, medicine, Humans, Repolarization, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, Flecainide, J wave, business.industry, Genetic Variation, medicine.disease, Anesthesia, Ventricular Fibrillation, Ventricular fibrillation, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Background: Early repolarization in the inferolateral leads has been recently recognized as a frequent syndrome associated with idiopathic ventricular fibrillation (VF). We report the case of a patient presenting dramatic changes in the ECG in association with recurrent VF in whom a novel genetic variant has been identified. Case Report: This young female (14 years) was resuscitated in 2001 following an episode of sudden death due to VF. All examinations including coronary angiogram with ergonovine injection, MRI, and flecainide or isoproterenol infusion were normal. The patient had multiple (>100) recurrences of VF unresponsive to beta-blockers, lidocaine/mexiletine, verapamil, and amiodarone. Recurrences of VF were associated with massive accentuation of the early repolarization pattern at times mimicking acute myocardial ischemia. Coronary angiography during an episode with 1.2 mV J/ST elevation was normal. Isoproterenol infusion acutely suppressed electrical storms, while quinidine eliminated all recurrences of VF and restored a normal ECG over a follow-up of 65 months. Genomic DNA sequencing of KATP channel genes showed missense variant in exon 3 (NC_000012) of the KCNJ8 gene, a subunit of the KATP channel, conferring predisposition to dramatic repolarization changes and ventricular vulnerability.
Published: 2009

22. Identification of thermal and rheological properties of an aeronautic epoxy resin-simulation of residual stresses

Author: Arnaud Poitou, F. Jaquemin, Y. Abou Msallem, Didier Delaunay, N. Boyard, and Stéphanie Chatel
Subjects: Materials science, technology, industry, and agriculture, Epoxy, Heat capacity, Thermal expansion, Thermal conductivity, Differential scanning calorimetry, Residual stress, visual_art, visual_art.visual_art_medium, General Materials Science, Composite material, Material properties, Curing (chemistry)
Abstract: An extensive material study of an aeronautic epoxy resin from commercial prepregs is reported in this article. The kinetics of the chemical reaction and the heat capacity are characterized by differential scanning calorimetry (DSC). The thermal conductivity, the thermal expansion coefficient, crosslinking heat flux and associated degree of cure, the volumetric shrinkage, the effective chemical shrinkage coefficient have been identified using a specific mold (named PVTα mold). Dynamic mechanical measurements are used to determine the rheological properties. The gel times at different curing temperatures are estimated. The degree of polymerization at the gel point is found to be independent of temperature. Finally, the residual stresses in a composite part are calculated using a finite element simulation and taking into account the evolution of the material properties, the temperature and degree of cure gradients during the curing process.
Published: 2008

23. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome

Author: Solena Le Scouarnec, Raluca Teusan, Stéphanie Bonnaud, Vincent Portero, Frederic Sacher, Sébastien Schmitt, Richard Redon, Jean-Baptiste Gourraud, Jade Violleau, Raphaël P. Martins, Julien Barc, Pierre Lindenbaum, Hervé Le Marec, Michel Haïssaguerre, Christian Dina, Estelle Baron, Lise Bellanger, Jean-Jacques Schott, Elodie Persyn, F. Kyndt, Philippe Mabo, Matilde Karakachoff, Vincent Probst, Stéphanie Chatel, Floriane Simonet, Laëtitia Duboscq-Bidot, Stéphane Bézieau, Xavier Daumy, Cardiology, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mathématiques Jean Leray (LMJL), Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire Traitement du Signal et de l'Image (LTSI), 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 [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Biology, White People, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetic variation, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, education, Molecular Biology, Allele frequency, Genetic Association Studies, Genetics (clinical), Brugada Syndrome, 030304 developmental biology, Brugada syndrome, 0303 health sciences, education.field_of_study, fungi, Cardiac arrhythmia, Arrhythmias, Cardiac, Sequence Analysis, DNA, General Medicine, Middle Aged, medicine.disease, 3. Good health, Minor allele frequency, Genes, Mutation, Ventricular fibrillation, cardiovascular system, Female
Abstract: International audience; The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20-30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes
Published: 2015

24. Prevalence and prognostic role of various conduction disturbances in patients with the Brugada syndrome

Author: Marc Delay, Vanina Bongard, Laurence Jesel, Jean-Marc Davy, Marie Sadron, Pierre Jaïs, Vincent Probst, Nicolas Derval, Frederic Sacher, Franck Raczka, Jean-Baptiste Gourraud, Arnaud Denis, Philippe Maury, Jean-Luc Pasquié, Alexandre Duparc, Anne Rollin, Michel Haïssaguerre, Christelle Cardin, Stéphanie Chatel, Pierre Mondoly, and Mélèze Hocini
Subjects: Male, medicine.medical_specialty, Asymptomatic, Sudden death, Electrocardiography, Heart Conduction System, Internal medicine, Confidence Intervals, Odds Ratio, Prevalence, Medicine, Humans, Brugada syndrome, Brugada Syndrome, Retrospective Studies, medicine.diagnostic_test, business.industry, ST elevation, Odds ratio, Right bundle branch block, Middle Aged, medicine.disease, Prognosis, Survival Rate, Death, Sudden, Cardiac, First-degree atrioventricular block, Cardiology, Female, France, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Prevalence and prognostic value of conduction disturbances in patients with the Brugada syndrome (BrS) remains poorly known. Electrocardiograms (ECGs) from 325 patients with BrS (47 ± 13 years, 258 men) with spontaneous (n = 143) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-six patients (70%) were asymptomatic, 73 patients (22%) presented with unexplained syncope, and 26 patients (8%) presented with sudden death or implantable cardioverter-defibrillator appropriated therapies at diagnosis or during a mean follow-up of 48 ± 34 months. P-wave duration of ≥120 ms was present in 129 patients (40%), first degree atrioventricular block (AVB) in 113 (35%), right bundle branch block (BBB) in 90 (28%), and fascicular block in 52 (16%). Increased P-wave duration, first degree AVB, and right BBB were more often present in patients after drug challenge than in patients with spontaneous type 1 ST elevation. Left BBB was present in 3 patients. SCN5A mutation carriers had longer P-wave duration and longer PR and HV intervals. In multivariate analysis, first degree AVB was independently associated with sudden death or implantable cardioverter-defibrillator appropriated therapies (odds ratio 2.41, 95% confidence interval 1.01 to 5.73, p = 0.046) together with the presence of syncope and spontaneous type 1 ST elevation. In conclusion, conduction disturbances are frequent and sometimes diffuse in patients with BrS. First degree AVB is independently linked to outcome and may be proposed to be used for individual risk stratification.
Published: 2013

25. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel

Author: Jean-Jacques Schott, Laurent Sallé, Julie Morel, Hui Liu, Patrice Bouvagnet, Hugues Abriel, Christophe Simard, Michel Lopez, Vincent Probst, Ninda Syam, Gilles Millat, Stéphanie Chatel, and Romain Guinamard
Subjects: Male, 030204 cardiovascular system & hematology, Arrhythmias, medicine.disease_cause, Cardiovascular, Biochemistry, Sodium Channels, Ion Channels, Membrane Potentials, Electrocardiography, 0302 clinical medicine, Brugada syndrome, Brugada Syndrome, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Immunochemistry, Right bundle branch block, Middle Aged, Recombinant Proteins, Electrophysiology, Medicine, Female, Research Article, Adult, medicine.medical_specialty, Science, Nonsense mutation, TRPM Cation Channels, 610 Medicine & health, Biology, Sudden death, Bifascicular block, 03 medical and health sciences, Molecular genetics, Cardiac conduction, medicine, Humans, Alleles, 030304 developmental biology, fungi, Proteins, Human Genetics, medicine.disease, Transmembrane Proteins, Death, Sudden, Cardiac, Genetics of Disease, Population Genetics
Abstract: Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ~14'000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.
Published: 2013

26. Parental electrocardiographic screening identifies a high degree of inheritance for congenital and childhood nonimmune isolated atrioventricular block

Author: Hervé Le Marec, Caroline Bonnet, Jean-René Lusson, Raphaël P. Martins, Jean-Jacques Schott, Francis Rouault, Alban-Elouen Baruteau, Jean-Benoit Thambo, Christian Dina, Elisabeth Villain, François Godart, Philippe Mabo, Vincent Probst, Alain Fraisse, François Marçon, Albin Behaghel, Véronique Gournay, Sophie Guillaumont, Yves Dulac, Jean-Marc Schleich, Stéphanie Chatel, Swanny Fouchard, Alain Chantepie, Béatrice Delasalle, Jean-Claude Daubert, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department de Chirurgie cardiaque des cardiopathies congénitales, Centre chirurgical Marie Lannelongue, Service de cardiologie et maladies vasculaires, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Traitement du Signal et de l'Image ( LTSI ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génie des procédés - environnement - agroalimentaire ( GEPEA ), Mines Nantes ( Mines Nantes ) -Université de Nantes ( UN ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ) -Centre National de la Recherche Scientifique ( CNRS ), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service cardiologie pédiatrique [Bordeaux], CHU Bordeaux [Bordeaux], Service de Cardiologie Infantile [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de cardiologie pédiatrique [Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Cabinet de Cardiologie pédiatrique, Service de cardiologie pédiatrique [Tours], CHU Tours, Service de cardiologie Pédiatrique [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de cardiologie Pédiatrique [Lille], Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service de cardiologie pédiatrique et congénitale adulte [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de cardiologie Pédiatrique [Marseille], Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service de cardiologie [Clermont-Ferrand], CHU Clermont-Ferrand, Service pédiatrie-cardiologie, CHU Toulouse [Toulouse]-Hôpital des Enfants, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), 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), Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Mines Nantes (Mines Nantes)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Cardiologie Maladies Vasculaires [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Toulouse [Toulouse], Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Chirurgical Marie Lannelongue (CCML), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Le Corre, Morgane, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: Male, Parents, MESH : Retrospective Studies, Heart malformation, MESH : NAV1.5 Voltage-Gated Sodium Channel, MESH : Prevalence, MESH : Aged, Electrocardiography, 0302 clinical medicine, MESH: Pregnancy, MESH : Child, Pregnancy, Prenatal Diagnosis, MESH: Child, Medicine, Sinus rhythm, genetics, Child, 0303 health sciences, MESH: Middle Aged, MESH: Genetic Testing, MESH : Infant, MESH: Infant, 3. Good health, MESH : Phenotype, MESH: Young Adult, MESH : Electrocardiography, Child, Preschool, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, conduction, MESH : Young Adult, Prenatal diagnosis, MESH: Phenotype, Sudden death, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), MESH : Adolescent, MESH : Genetic Testing, Humans, MESH : Middle Aged, Genetic Testing, MESH: Prenatal Diagnosis, MESH : Prenatal Diagnosis, MESH: Prevalence, Aged, Retrospective Studies, [SDV.IB] Life Sciences [q-bio]/Bioengineering, MESH: Adolescent, MESH: Parents, MESH: Humans, MESH: Child, Preschool, MESH : Humans, Infant, MESH: Adult, MESH: Retrospective Studies, medicine.disease, MESH : Pregnancy, MESH : Genetic Predisposition to Disease, Atrioventricular block, MESH: Female, Pediatrics, ECG screening, 030204 cardiovascular system & hematology, MESH : Child, Preschool, NAV1.5 Voltage-Gated Sodium Channel, atrioventricular block, Prevalence, Mass Screening, MESH : Female, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, Family history, MESH : Parents, MESH: Aged, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, Middle Aged, MESH : Adult, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Atrioventricular Block, Phenotype, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, medicine.symptom, Adult, Adolescent, pediatrics, MESH : Male, MESH : Infant, Newborn, Asymptomatic, Young Adult, MESH: Atrioventricular Block, Genetic Predisposition to Disease, MESH: Mass Screening, PR interval, 030304 developmental biology, MESH : Mass Screening, business.industry, Infant, Newborn, MESH: NAV1.5 Voltage-Gated Sodium Channel, MESH: Male, MESH: Electrocardiography, business
Abstract: Background— The origin of congenital or childhood nonimmune isolated atrioventricular (AV) block remains unknown. We hypothesized that this conduction abnormality in the young may be a heritable disease. Methods and Results— A multicenter retrospective study (13 French referral centers, from 1980–2009) included 141 children with AV block diagnosed in utero, at birth, or before 15 years of age without structural heart abnormalities and without maternal antibodies. Parents and matched control subjects were investigated for family history and for ECG screening. In parents, a family history of sudden death or progressive cardiac conduction defect was found in 1.4% and 11.1%, respectively. Screening ECGs from 130 parents (mean age 42.0±6.8 years, 57 couples) were compared with those of 130 matched healthy control subjects. All parents were asymptomatic and in sinus rhythm, except for 1 with undetected complete AV block. Conduction abnormalities were more frequent in parents than in control subjects, found in 50.8% versus 4.6%, respectively ( P P P P SCN5A mutation screening identified 2 mutations in 2 patients among 97 children. Conclusions— ECG screening in parents of children affected by idiopathic AV block revealed a high prevalence of conduction abnormalities. These results support the hypothesis of an inheritable trait in congenital and childhood nonimmune isolated AV block.
Published: 2012

27. Identification of a strong genetic background for progressive cardiac conduction defect by epidemiological approach

Author: Karim Gacem, Florence Kyndt, Vincent Probst, Estelle Baron, Jean-Jacques Schott, Swanny Fouchard, Jean Marc Dupuis, Stéphanie Chatel, Jean-Pierre Cebron, Aurelie Longueville, Hervé Le Marec, Matilde Karakachoff, Philippe Jaafar, Claude Gully, Jean-Baptiste Gourraud, Eric Rendu, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Cardiologie [La Roche-sur-Yon], Centre Hospitalier Départemental site de la Roche-sur-Yon (CHD de la Roche-sur-Yon), Service Cardiologie et Maladies Vasculaires [CH de Cholet], Centre Hospitalier de Cholet, Service Cardiologie et Maladies Vasculaires [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Consiglio Nazionale delle Ricerche - CNR [Pisa, Italia], Istituto di Fisiologia Clinica - IFC [Pisa, Italia], Service Cardiologie et Maladies Vasculaires [NCN Nantes], Nouvelles Cliniques Nantaises - NCN [Nantes], P.H.R.C. 2004 R20/07 and 2011 from the CHU de Nantes, France. DGOS-PHRC., CHATEL, Stephanie, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), and CHU de Nantes, l'Institut du Thorax, CIC
Subjects: Adult, Pediatrics, medicine.medical_specialty, Pathology, Pacemaker, Artificial, Disease, 030204 cardiovascular system & hematology, NAV1.5 Voltage-Gated Sodium Channel, 03 medical and health sciences, 0302 clinical medicine, Heart Conduction System, Epidemiology, medicine, Humans, 030304 developmental biology, Aged, 0303 health sciences, Molecular Epidemiology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Family aggregation, Middle Aged, 3. Good health, Pedigree, Genetics, Population, Heart Block, Mutation, Progressive cardiac conduction defect, France, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; INTRODUCTION:Progressive cardiac conduction defect (PCCD) is a frequent disease attributed to degeneration and fibrosis of the His bundle. Over the past years, gene defects have been identified demonstrating that PCCD could be a genetic disease. The aim of this study was to show a familial aggregation for PCCD using a genetic epidemiological approach to improve in fine genetic knowledge of the transmission of the disease.METHODS AND RESULTS:Using the French social security number, the authors have been able to determine the city of birth of the 6667 patients implanted with a pacemaker (PM) for PCCD between 1995 and 2005 in the western part of France. The authors then mapped the frequency of PM implantations for PCCD. A large heterogeneity of the frequency of the disease has been observed, with a frequency of 0.21% in the major city (Nantes) ranging up to 2.28% in specific parishes. Familial studies performed in the parishes with the highest frequency of the disease allowed the authors to identify five large families with PCCD. Clinical investigations demonstrated phenotype heterogeneity between families. Three patterns have been differentiated.CONCLUSIONS:This study demonstrates a disparate geographical repartition of the frequency of PM implantation in the area of the authors at least in part related to a hereditary factor. The identification of five large families affected by PCCD using epidemiological approach underlines the existence of a major genetic background in PCCD.
Published: 2012

28. Identification of large families in early repolarization syndrome

Author: Michel Haïssaguerre, Hervé Le Marec, Solena Le Scouarnec, Frederic Sacher, Juan E. Sandoval, Nicolas Derval, Vincent Probst, Jean-Jacques Schott, Philippe Mabo, Jean-Baptiste Gourraud, Pascal Chavernac, Stéphanie Chatel, Richard Redon, Vincent Portero, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
Subjects: Proband, Male, Benign early repolarization, medicine.medical_treatment, Disease, 030204 cardiovascular system & hematology, early repolarization syndrome, Electrocardiography, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Heart Rate, Valsalva maneuver, MESH: Syndrome, 030212 general & internal medicine, Young adult, MESH: Heart Rate, MESH: Aged, MESH: Middle Aged, medicine.diagnostic_test, Syndrome, Middle Aged, 3. Good health, Pedigree, MESH: Arrhythmias, Cardiac, familial inheritance, MESH: Young Adult, Cardiology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Cardiology and Cardiovascular Medicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, MESH: Valsalva Maneuver, Adult, medicine.medical_specialty, Adolescent, MESH: Pedigree, Valsalva Maneuver, 03 medical and health sciences, Young Adult, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Heart rate, medicine, Humans, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Adult, MESH: Death, Sudden, Cardiac, Arrhythmias, Cardiac, medicine.disease, ventricular fibrillation, MESH: Male, MESH: Electrocardiography, Endocrinology, Death, Sudden, Cardiac, Ventricular fibrillation, business, MESH: Female
Abstract: International audience; OBJECTIVES: The aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease. BACKGROUND: Early repolarization (ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated. METHODS: We screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern. RESULTS: Twenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern. CONCLUSIONS: ERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed.
Published: 2012

29. 341 Parental electrocardiographic screening identifies a high degree of inheritance for congenital and childhood non-immune isolated atrioventricular block

Author: Alain Fraisse, Albin Behaghel, Jean-Marc Schleich, Swanny Fouchard, Alban-Elouen Baruteau, Vincent Probst, Francis Rouault, Yves Dulac, Alain Chantepie, Jean-René Lusson, Christian Dina, Raphaël P. Martins, Elisabeth Villain, François Godart, Sophie Guillaumont, Jean-Claude Daubert, Caroline Bonnet, Stéphanie Chatel, Jean-Jacques Schott, Véronique Gournay, Jean-Benoit Thambo, Hervé Le Marec, François Marçon, and Philippe Mabo
Subjects: Genetics, Inheritance (object-oriented programming), Immune system, business.industry, medicine, medicine.disease, business, Cardiology and Cardiovascular Medicine, Atrioventricular block, Degree (temperature)
Published: 2012
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30. On the Equivalent In-Plane Permeabiliy

Author: F. Chinesta, Arnaud Poitou, Ll. Gascón, Juan Antonio Marín García, Stéphanie Chatel, Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), EADS IW, and Universitat Politècnica de València (UPV)
Subjects: Work (thermodynamics), 010304 chemical physics, business.industry, Degrees of freedom, Mathematical analysis, RTM, Computational intelligence, Structural engineering, [SPI.MECA]Engineering Sciences [physics]/Mechanics [physics.med-ph], 3D modeling, 01 natural sciences, Permeability, 010305 fluids & plasmas, [SPI.MAT]Engineering Sciences [physics]/Materials, Permeability (earth sciences), In plane, Dimension (vector space), Separated Representations, 0103 physical sciences, General Materials Science, Model Reduction, business, Anisotropy, Mathematics
Abstract: International audience; Simulation of RTM processes is usually performed in 2D. Thus, only a mesh of the middle plane is needed with the associated degrees of freedom savings with respect to fully 3D modeling. However such modeling needs the definition of an equivalent in-plane permeability representing the ignored dimension (the thickness). The definition of such permeability is not a trivial task because each ply in the thickness direction can be anisotropic, being the principal anisotropy direction different from one ply to the neighbor plies. In this work we propose a novel fully 3D modeling whose computational cost is equivalent to a 2D solution. It allows addressing properly the equivalent in-plane permeability issue.
Published: 2010

31. 325 Clinical presentation and long-term clinical outcomes of non immune, isolated atrioventricular block diagnosed in utero or early childhood

Author: Caroline Bonnet, Francis Rouault, Hervé Le Marec, Alban-Elouen Baruteau, Albin Behaghel, Swanny Fouchard, Yves Dulac, François Marçon, Jean-René Lusson, Sophie Guillaumont, Alain Chantepie, Philippe Mabo, Jean-Benoit Thambo, Christophe Leclercq, Jean-Claude Daubert, Elisabeth Villain, François Godart, Alain Fraisse, Jean-Jacques Schott, Jean-Marc Schleich, Véronique Gournay, Vincent Probst, and Stéphanie Chatel
Subjects: Pediatrics, medicine.medical_specialty, business.industry, medicine.disease, Term (time), Immune system, In utero, embryonic structures, Medicine, Early childhood, Presentation (obstetrics), business, Cardiology and Cardiovascular Medicine, Atrioventricular block, reproductive and urinary physiology
Published: 2012
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32. GAIN-OF-FUNCTION MUTATION IN THE VOLTAGE-GATED K+ CHANNEL BETA-2 SUBUNIT IS ASSOCIATED WITH BRUGADA SYNDROME

Author: Isabelle Baró, Richard Redon, J. Sandoval-Tortosa, Philippe Mabo, Vincent Probst, S. Le Scouarnec, Christian Dina, Carol Scott, Jean-Baptiste Gourraud, Pierre Lindenbaum, Sophie Burel, Zeineb Es-Salah-Lamoureux, Jade Violleau, Thomas O'Hara, Vincent Portero, Stéphanie Bonnaud, Jean-Jacques Schott, Flavien Charpentier, Stéphanie Chatel, Gildas Loussouarn, Floriane Simonet, H. Le Marec, and Céline Marionneau
Subjects: Voltage-gated ion channel, business.industry, Physiology (medical), Protein subunit, medicine, Gain of function mutation, Cardiology and Cardiovascular Medicine, Beta (finance), medicine.disease, business, Molecular biology, K channels, Brugada syndrome
Published: 2014

33. G024 Implication des canaux KATP dans le syndrome de repolarisation précoce

Author: Vincent Probst, H. Le Marec, Michel Haïssaguerre, Jean-Jacques Schott, R. Liersch, Eric Schulze-Bahr, Stéphanie Chatel, Frederic Sacher, Arthur A.M. Wilde, Gildas Loussouarn, Rukshen Weerasooriya, Marc Horlitz, and Stefan Kääb
Subjects: business.industry, Medicine, General Medicine, business, Cardiology and Cardiovascular Medicine, Molecular biology
Abstract: La repolarisation precoce est une caracteristique electro cardiographique commune (1-5 % de la population generale). Une etude recente a montre que l’incidence de la repolarisation precoce (RP) est plus elevee chez les sujets ayant presente une fibrillation ventriculaire (31 % des patients vs 5 % des controles). A ce jour, il est encore impossible de differencier les patients presentant un aspect de RP a risque parmi la population generale. L’existence de forme familiale de RP associee a des morts subites suggere un caractere hereditaire a cette pathologie. Une etude genetique a ete realisee sur une cohorte de 96 patients. Les genes majeurs des troubles du rythme cardiaque et les genes codant les canaux ioniques impliques dans la phase de repolarisation du potentiel d’action ventriculaire ont ete exclus par sequencage chez ces patients. Les canaux potassiques ATP dependant (KATP) sont fortement exprimes dans les cardiomyocytes. L’une des hypotheses emises est qu’une augmentation de 1-2 % de l’ouverture de ces canaux genererait un courant suffisant qui pourrait affecter la phase de repolarisation ventriculaire. Les canaux KATP sont composes de sous-unites canalaires Kir6.0 (KCNJ8 codant Kir6.1 ou KCNJ11 codant Kir6.2) et de recepteurs aux sulphonylurees SUR (ABCC8 codant SUR1 ou ABCC9 codant SUR2). L’approche gene-candidat a permis de mettre en evidence le variant rare p.S422L dans le gene KCNJ8 chez une jeune patiente presentant de nombreux episodes de fibrillation ventriculaire (plus de 100) et une RP dans les derivations infero-laterales. Suite a ces premiers resultats, nous avons sequences les autres sous-unites des canaux KATP. Ainsi, 5 variants ont ete identifies dans le gene ABCC9 : 4 variants faux-sens et une substitution d’un nucleotide dans un site d’epissage. L’enquete familiale et l’analyse fonctionnelle sont en cours pour ces patients. Plusieurs hypotheses physiopathologiques (augmentation du trafic membranaire, diminution de la sensibilite a l’ATP…) vont etre testees afin de comprendre l’implication de ces variants sur le potentiel d’action ventriculaire. L’identification de 6 patients sur 96 (6.25 %) porteurs de variant dans les genes codant les canaux KATP conforte l’hypothese du role de ce courant dans le syndrome de repolarisation precoce.
Published: 2009
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34. Erratum: Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author: Connie R. Bezzina, Kanae Hasegawa, Tohru Minamino, Peter Weeke, Rachel Bastiaenen, Jean-Jacques Schott, Rianne Wolswinkel, Olivier Lantieri, Vincent M. Christoffels, Simon Lecointe, Wataru Shimizu, Véronique Fressart, Richard Redon, Philippe Froguel, Lia Crotti, Charles Antzelevitch, Morten S. Olesen, Manfred Gessler, Stéphanie Chatel, Dan M. Roden, Beverley Balkau, Arie O. Verkerk, Britt M. Beckmann, Jade Violleau, Stéphane Bézieau, Arthur A.M. Wilde, Ruben Coronel, David Weber, Christian Dina, Hiroshi Watanabe, Pierre Lindenbaum, Stefan Kääb, Julien Barc, Aurore Despres, Peter J. Schwartz, Eric Charpentier, Carol Ann Remme, Akihiko Nogami, Minoru Horie, Margherita Torchio, Sven Zumhagen, Françoise Gros, Naomasa Makita, Florence Kyndt, Cornelia Wiese, Vincent Probst, Naoto Endo, Takeshi Aiba, Hervé Le Marec, Susan Bartkowiak, Bas J. Boukens, Seiko Ohno, Eric Schulze-Bahr, Pascale Guicheney, Antoine Leenhardt, Vincent Portero, Hanno L. Tan, Yuka Mizusawa, Jacob Tfelt-Hansen, Elijah R. Behr, Floriane Simonet, Jean-Baptiste Gourraud, and Federica Dagradi
Subjects: Genetics, medicine, Biology, HEY2, medicine.disease, Sudden cardiac death, Brugada syndrome, Rare disease
Published: 2013

35. Mutations in the SCN5A promoter associated with Brugada syndrome

Author: Stéphanie Chatel, Connie R. Bezzina, Naomasa Makita, Nobue Yagihara, Hiroshi Watanabe, Phil Barnett, Minoru Horie, Wataru Shimizu, Jean-Jacques Schott, and Tohru Minamino
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, business.industry, Promoter, medicine.disease, Chromatin, Open reading frame, CTCF, Transcription (biology), Medicine, Coding region, cardiovascular diseases, Cardiology and Cardiovascular Medicine, business, Transcription factor, Brugada syndrome
Abstract: Purpose: Loss-of-function-mutations in the coding sequence of SCN5A, which encodes the α-subunit of predominant cardiac Na+ channels, have been associated with Brugada syndrome and decreased expression of Na+ channels by mutations in SCN5A is one of the mechanisms. However, the majority of patients are genotype-negative in Brugada syndrome. Here, we tested the hypothesis that variants in the promoter region of SCN5A also contribute to susceptibility to Brugada syndrome. Methods: We resequenced the core-promoter region of SCN5A (∼2.8 kb) in 503 patients with Brugada syndrome. We studied the effects of identified variants on promoter activity using luciferase reporter assay in heterologous expression system. We mapped the promoter variants to the mouse genome and studied the association with key factors of the transcriptional machinery using ChIP-Seq analyses. Results: We identified 18 novel rare variants in the SCN5A promoter in 19 unrelated patients with Brugada syndrome. All variants were absent in >2,500 controls. Using luciferase reporter assay, 5 promoter variants were functionally characterized, and each displayed significant decrease of promoter activity (57±17% of wild-type) compared to wild-type sequences. ChIP-Seq analyses revealed that majority of these promoter variants, for which the wild-type nucleotide is conserved, are located at the regions directly bound by the transcription factors that are important for the development and function of heart including TBX3, TBX5, and NKX2-5, and by the chromatin and insulator associated factor CTCF, important for insulator establishment and chromatin looping regulation. Conclusions: Variants in the core-promoter region of SCN5A were identified in patients with Brugada syndrome and were associated with the decreased promoter activity. Altered SCN5A transcription levels, possibly by negative consequences for the binding of transcription factors to the promoter region, may modulate susceptibility to Brugada syndrome.
Published: 2013

36. Risk Stratification and Therapeutic Approach in Brugada Syndrome

Author: Vincent Probst, Stéphanie Chatel, Jean-Baptiste Gourraud, and Hervé Le Marec
Subjects: medicine.medical_specialty, business.industry, medicine.medical_treatment, Implantable cardioverter-defibrillator, medicine.disease, Sudden death, Asymptomatic, Ajmaline, Therapeutic approach, Physiology (medical), Internal medicine, medicine, Cardiology, Clinical Arrhythmias, ST segment, medicine.symptom, Cardiology and Cardiovascular Medicine, Complication, business, medicine.drug, Brugada syndrome
Abstract: Brugada syndrome (BrS) is a clinical entity characterised by an incomplete right bundle branch block associated with an ST segment elevation in the right precordial leads and a risk of ventricular arrhythmia and sudden death in the absence of structural abnormalities. Patients with a personal history of sudden death have an annual arrhythmia risk of recurrence as high as 10 %. Similarly, the presence of syncope is consistently associated with an increased arrhythmic risk. This risk can be estimated at about 1.5 % per year. The risk is lower in asymptomatic patients. Regarding the relatively high rate of complication of Implantable cardioverter defibrillator (ICD) implantation, in most of the cases, asymptomatic patients with a Brugada syndrome revealed during ajmaline challenge do not need to be implanted. The situation is more complex in patients with a spontaneous type 1 aspect since the risk could be estimated to be around 0.8 % per year. For these patients, a careful evaluation of the arrhythmic risk using all the different tools available is mandatory.
Published: 2012

37. Prediction of Unruptured Intracranial Aneurysm Evolution: The UCAN Project

Author: Romain Bourcier, Zeineb Lamoureux, Alban Gaignard, Olivier Naggara, Florent Autrusseau, Stéphanie Chatel, Gervaise Loirand, Myriam Edjlali, Richard Redon, Anne-Clémence Vion, Vincent L'Allinec, Emmanuelle Bourcereau, Hubert Desal, Matilde Karakachoff, Solène Jouan, Autrusseau, Florent, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and PHRC-19-0394_UCAN
Subjects: Male, medicine.medical_specialty, Consensus, Imaging data, Aneurysm, Predictive Value of Tests, Risk Factors, medicine, Medical imaging, Humans, Arterial wall, Prospective Studies, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Retrospective cohort study, Intracranial Aneurysm, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical Practice, Cohort, Surgery, Female, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: BACKGROUND Management of small (

38. Comparison between flecainide and ajmaline challenge in Brugada syndrome patients

Author: Jacques Mansourati, Frederic Sacher, H. Le Marec, Philippe Mabo, Vincent Probst, Jean-Baptiste Gourraud, Stéphanie Chatel, and D. Babuty
Subjects: medicine.medical_specialty, Continuous infusion, business.industry, medicine.disease, QT interval, Ajmaline, QRS complex, Anesthesia, Internal medicine, Heart rate, medicine, Cardiology, Sinus rhythm, Cardiology and Cardiovascular Medicine, business, Flecainide, medicine.drug, Brugada syndrome
Abstract: Background: Flecainide and ajmaline challenges are used to unmask the aspect of Brugada syndrome. There is no direct comparison of the electrocardiographic modification induced by these two drugs in the large population of patients. These two drugs are used in our reference center which allows a comparison of results. Methods: Injections are performed by continuous infusion over a period of 10 minutes at 1mg/kg dose for ajmaline and 2 mg/kg for flecainide. Tests were performed in case of absence of type 1 aspect on the resting ECG and in absence of major conduction defects Results: The flecainide test (F) was performed in 412 patients and ajmaline test (A) in 311. Mean age was 41±16 years and 42±16 years in A (p = 0.2) and there was 194 women in group F (47%) vs 152 in group A (48%), NS. All patients were in sinus rhythm in both groups. Heart rate was similar 70±12 vs 71±12 bpm (p = 0.17). There was no difference between the two groups for heart rate 70±12 vs 71±13 bpm (p=0.17), PR 161±28 ms vs 162±29 ms (p=0.63), QRS 95±20 ms vs 96±13 ms (p= 0.94). The QTc appears to be longer in the F than in the A group 409±29 vs 418±28 ms (p

39. TRPM4 Genetic Variants in Patients with Congenital Atrio-Ventricular Block

Author: Valentin Sottas, Ninda Syam, Jean-Sébastien Rougier, Jean-Jacques Schott, Alban Baruteau, Hugues Abriel, Vincent Probst, and Stéphanie Chatel
Subjects: Membrane potential, Genetics, Candidate gene, Transient receptor potential channel, Sodium channel, Cardiac conduction, Mutant, Biophysics, Depolarization, Biology, Electrical conduction system of the heart, Molecular biology
Abstract: Background: Transient Receptor Potential Subfamily Melastatin Member 4 (TRPM4) is a non-selective cardiac cation channel. Mutations in its gene cause cardiac conduction disease. The mechanisms underlying TRPM4-dependent conduction disorders are not fully understood.Aim: To investigate genetic variants of TRPM4 from congenital atrio-ventricular block (cAVB) patients.Methods and Results: Ninety-five cAVB patients were screened for candidate genes. We found 6 genetic variants in TRPM4. In whole-cell patch-clamp configuration, TRPM4 displays two current phases after patch rupture: transient (tr) and plateau (pl). Two cAVB mutants, p.A432T and p.A432T;G582S, showed lower protein expression (29±4% and 17±7% n=4) and one, p.G582S, showed higher expression (177±15% n=4) compared to WT. Interestingly, only the plateau phase matches the protein expression profile (p.A432T 241±23pA/pF n=6, p.G582S 994±118pA/pF n=6 vs. WT 580±66pA/pF n=20). Lower incubation temperature (28°C for 24h), which compromises protein quality control, rescued low expressing mutants, both at protein (p.A432T 72±8% and p.A432T;G582S 65±7% n=3) and functional (p.A432T 600±114pA/pF n=6 vs. WT 639±116pA/pF n=4) levels. We studied whether ubiquitylation plays a role in this loss-of-expression. Despite being ubiquitylated, no link between ubiquitylation and TRPM4 expression could be observed.Conclusions: TRPM4 mutations in cAVB patients cause loss- or gain-of-function. Analogous to the supernormal conduction phenomenon, we speculate that increase or decrease of its activity in the conduction system may hyperpolarize or depolarize the resting membrane potential; thus, reducing the availability of sodium channels and subsequently leading to conduction slowing and clinical phenotype.
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40. Moment estimators of relatedness from low-depth whole-genome sequencing data

Author: Herzig, Anthony, Ciullo, M., Leutenegger, A-L., Perdry, H., Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institute of Genetics and Biophysics 'A. Buzzati Traverso' [Naples, Italy], Consiglio Nazionale delle Ricerche [Roma] (CNR), Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, FranceGenRef Consortium: Jean-François Deleuze, Emmanuelle Génin, Richard Redon, Chantal Adjou, Stéphanie Chatel, Claude Férec, Marcel Goldberg, Philippe-Antoine Halbout, Hervé Le Marec, David L'Helgouach, Karen Rouault, Jean-Jacques Schott, Anne Vogelsperger, Marie Zins, Delphine Bacq, Hélène Blanchet, Anne Boland, Pierre Lindenbaum, Thomas Ludwig, Vincent Meyer, Robert Olaso, Lourdes Velo-Suárez, Isabel Alves, Ozvan Bocher, Christian Dina, Anthony F Herzig, Matilde Karakachoff, Gaëlle Marenne, Aude Saint Pierre, and PODEUR, Sophie
Subjects: Genotype, Models, Genetic, Whole Genome Sequencing, [SDV]Life Sciences [q-bio], Applied Mathematics, Low-depth, Biochemistry, Pedigree, Computer Science Applications, [SDV] Life Sciences [q-bio], Fraternity coefficient, Genotype likelihoods, Structural Biology, Kinship, Humans, Computer Simulation, Moment estimators, Sequencing data, Molecular Biology, Software
Abstract: Background Estimating relatedness is an important step for many genetic study designs. A variety of methods for estimating coefficients of pairwise relatedness from genotype data have been proposed. Both the kinship coefficient $$\varphi$$ φ and the fraternity coefficient $$\psi$$ ψ for all pairs of individuals are of interest. However, when dealing with low-depth sequencing or imputation data, individual level genotypes cannot be confidently called. To ignore such uncertainty is known to result in biased estimates. Accordingly, methods have recently been developed to estimate kinship from uncertain genotypes. Results We present new method-of-moment estimators of both the coefficients $$\varphi$$ φ and $$\psi$$ ψ calculated directly from genotype likelihoods. We have simulated low-depth genetic data for a sample of individuals with extensive relatedness by using the complex pedigree of the known genetic isolates of Cilento in South Italy. Through this simulation, we explore the behaviour of our estimators, demonstrate their properties, and show advantages over alternative methods. A demonstration of our method is given for a sample of 150 French individuals with down-sampled sequencing data. Conclusions We find that our method can provide accurate relatedness estimates whilst holding advantages over existing methods in terms of robustness, independence from external software, and required computation time. The method presented in this paper is referred to as LowKi (Low-depth Kinship) and has been made available in an R package (https://github.com/genostats/LowKi).
Published: 2022

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