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3. The genetics underlying acquired long QT syndrome: impact for genetic screening

Author

Itoh, Hideki, Crotti, Lia, Aiba, Takeshi, Spazzolini, Carla, Denjoy, Isabelle, Fressart, Véronique, Hayashi, Kenshi, Nakajima, Tadashi, Ohno, Seiko, Makiyama, Takeru, Wu, Jie, Hasegawa, Kanae, Mastantuono, Elisa, Dagradi, Federica, Pedrazzini, Matteo, Yamagishi, Masakazu, Berthet, Myriam, Murakami, Yoshitaka, Shimizu, Wataru, Guicheney, Pascale, Schwartz, Peter J., and Horie, Minoru

Published
2016
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4. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

Author

Kapplinger, Jamie D., Tester, David J., Alders, Marielle, Benito, Begoña, Berthet, Myriam, Brugada, Josep, Brugada, Pedro, Fressart, Véronique, Guerchicoff, Alejandra, Harris-Kerr, Carole, Kamakura, Shiro, Kyndt, Florence, Koopmann, Tamara T., Miyamoto, Yoshihiro, Pfeiffer, Ryan, Pollevick, Guido D., Probst, Vincent, Zumhagen, Sven, Vatta, Matteo, Towbin, Jeffrey A., Shimizu, Wataru, Schulze-Bahr, Eric, Antzelevitch, Charles, Salisbury, Benjamin A., Guicheney, Pascale, Wilde, Arthur A.M., Brugada, Ramon, Schott, Jean-Jacques, and Ackerman, Michael J.

Published
2010
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5. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Author

Behr, Elijah R., Savio-Galimberti, Eleonora, Barc, Julien, Holst, Anders G., Petropoulou, Evmorfia, Prins, Bram P., Jabbari, Javad, Torchio, Margherita, Berthet, Myriam, Mizusawa, Yuka, Yang, Tao, Nannenberg, Eline A., Dagradi, Federica, Weeke, Peter, Bastiaenan, Rachel, Ackerman, Michael J., Haunso, Stig, Leenhardt, Antoine, Kääb, Stefan, Probst, Vincent, Redon, Richard, Sharma, Sanjay, Wilde, Arthur, Tfelt-Hansen, Jacob, Schwartz, Peter, Roden, Dan M., Bezzina, Connie R., Olesen, Morten, Darbar, Dawood, Guicheney, Pascale, Crotti, Lia, and Jamshidi, Yalda

Published
2015
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7. Réactivation de l'épicarde à l'origine de l'infiltration fibro-adipeuse dans la cardiomyopathie atriale

Author

Suffee, Nadine, Moore-Morris, Thomas, Jagla, Bernd, Mougenot, Nathalie, Dilanian, Gilles, Berthet, Myriam, Proukhnitzky, Julie, Leprince, Pascal, Tregouet, David-Alexandre, Puceat, Michel, Hatem, Stéphane, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Phénotypage du petit animal (UMS28), Université Pierre et Marie Curie - Paris 6 (UPMC), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the French National Agency through the national program Investissements d’Avenir Grant ANR-10-IAHU-05 (to N. Suffee, G. Dilanian, M. Berthet, D.A. Tregouet, P. Le Prince, and S.N. Hatem) and through the RHU-CARMMA Grant ANR-15-RHUS-0003 and the Fondation de La Recherche Medicale (to N. Suffee and S.N. Hatem). This project received funding from the European Union’s Horizon 2020 Research Programme, Grant 633193 CATCH ME (N. Suffee and S.N. Hatem). We thank The Leducq Fondation for its continuous support of our research and generously awarding us for cell imaging facility (M. Pucéat, Equipement de Recherche et Plateformes Technologiques (ERPT)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-15-RHUS-0003,CARMMA,Role de la sénescence du tissu adipeux dans les co-morbidités des pathologies métaboliques(2015), European Project: 633193,NHMRC::NHMRC Postgraduate Scholarships(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]

Subjects
[SDV]Life Sciences [q-bio], [SDV.BA]Life Sciences [q-bio]/Animal biology, cardiovascular system, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract

International audience; Rationale: Fibro-fatty infiltration of sub-epicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation (AF). Objective: Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process. Methods and Results: 109 human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibrofatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or AF when compared to patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells co-expressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilm's Tumor-1 (WT1)CreERT2/+;ROSA-tdT+/- mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells (aEPDCs) expressing Platelet-derived growth factor receptor-alpha (PDGFRalpha were isolated and differentiated into myofibroblasts in the presence of angiotensin-II. Furthermore, single cell RNA-seqencing analysis identified several clusters of aEPDCs and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. Conclusions:Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of aEPDCs, pre-programmed towards a specific cell fate, contribute to fibro-fatty infiltration of sub-epicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of AF.

Published
2020
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11. Association of Serum Cholesterol Efflux Capacity With Mortality in Patients With ST-Segment Elevation Myocardial Infarction

Author

Guerin, Maryse, primary, Silvain, Johanne, additional, Gall, Julie, additional, Darabi, Maryam, additional, Berthet, Myriam, additional, Frisdal, Eric, additional, Hauguel-Moreau, Marie, additional, Zeitouni, Michel, additional, Kerneis, Mathieu, additional, Lattuca, Benoit, additional, Brugier, Delphine, additional, Collet, Jean-Philippe, additional, Lesnik, Philippe, additional, and Montalescot, Gilles, additional

Published
2018
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12. Differentiation and quantification of fibrosis, fat and fatty fibrosis in human left atrial myocardium using ex vivo MRI

Author

Bouazizi, Khaoula, primary, Rahhal, Amer, additional, Kusmia, Slawomir, additional, Evin, Morgane, additional, Defrance, Carine, additional, Cluzel, Philippe, additional, Berthet, Myriam, additional, Atassi, Fabrice, additional, Leprince, Pascal, additional, Lebreton, Guillaume, additional, Kachenoura, Nadjia, additional, Hatem, Stéphane N., additional, and Redheuil, Alban, additional

Published
2018
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13. Cardiac MR Strain: A Noninvasive Biomarker of Fibrofatty Remodeling of the Left Atrial Myocardium

Author

Huber, Adrian T., primary, Lamy, Jérôme, additional, Rahhal, Amer, additional, Evin, Morgane, additional, Atassi, Fabrice, additional, Defrance, Carine, additional, Lebreton, Guillaume, additional, Clément, Karine, additional, Berthet, Myriam, additional, Isnard, Richard, additional, Leprince, Pascal, additional, Cluzel, Philippe, additional, Hatem, Stéphane N., additional, Kachenoura, Nadjia, additional, and Redheuil, Alban, additional

Published
2018
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14. Role of common and rare variants in SCN10A:results from the Brugada syndrome QRS locus gene discovery collaborative study

Author

Behr, Elijah R., Savio-Galimberti, Eleonora, Barc, Julien, Holst, Anders G., Petropoulou, Evmorfia, Prins, Bram P., Jabbari, Javad, Torchio, Margherita, Berthet, Myriam, Mizusawa, Yuka, Yang, Tao, Nannenberg, Eline A., Dagradi, Federica, Weeke, Peter, Bastiaenan, Rachel, Ackerman, Michael J., Haunso, Stig, Leenhardt, Antoine, Kääb, Stefan, Probst, Vincent, Redon, Richard, Sharma, Sanjay, Wilde, Arthur, Tfelt-Hansen, Jacob, Schwartz, Peter, Roden, Dan M., Bezzina, Connie R., Olesen, Morten, Darbar, Dawood, Guicheney, Pascale, Crotti, Lia, Jamshidi, Yalda, Behr, Elijah R., Savio-Galimberti, Eleonora, Barc, Julien, Holst, Anders G., Petropoulou, Evmorfia, Prins, Bram P., Jabbari, Javad, Torchio, Margherita, Berthet, Myriam, Mizusawa, Yuka, Yang, Tao, Nannenberg, Eline A., Dagradi, Federica, Weeke, Peter, Bastiaenan, Rachel, Ackerman, Michael J., Haunso, Stig, Leenhardt, Antoine, Kääb, Stefan, Probst, Vincent, Redon, Richard, Sharma, Sanjay, Wilde, Arthur, Tfelt-Hansen, Jacob, Schwartz, Peter, Roden, Dan M., Bezzina, Connie R., Olesen, Morten, Darbar, Dawood, Guicheney, Pascale, Crotti, Lia, and Jamshidi, Yalda

Abstract

AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970).CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

Published
2015

15. MOG1

Author

Kattygnarath, Darouna, Maugenre, Svetlana, Neyroud, Nathalie, Balse, Elise, Ichai, Carole, Denjoy, Isabelle, Dilanian, Gilles, Martins, Raphael, Fressart, Véronique, Berthet, Myriam, Schott, Jean Jacques, Leenhardt, Antoine, Probst, Vincent, Le Marec, Herve, Hainque, Bernard, Coulombe, Alain, Hatem, Stéphane, Guicheney, Pascale, Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires [CHU Pitié-Salpétriêre], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de cardiologie (APHP-Hôpital Lariboisière), Hôpital Lariboisière-APHP, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, MESH: Humans, MESH: Molecular Sequence Data, MESH: Rats, MESH: Transfection, fungi, MESH: Genetic Predisposition to Disease, MESH: Sequence Alignment, MESH: Myocytes, Cardiac, MESH: NAV1.5 Voltage-Gated Sodium Channel, MESH: Amino Acid Sequence, MESH: Rats, Wistar, MESH: ran GTP-Binding Protein, MESH: Electrocardiography, MESH: Sodium Channels, MESH: Brugada Syndrome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: HEK293 Cells, MESH: Patch-Clamp Techniques, cardiovascular system, MESH: Animals, cardiovascular diseases, MESH: DNA Mutational Analysis, MESH: Female
Abstract

International audience; Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS.

Published
2011
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16. The genetics underlying acquired long QT syndrome: impact for genetic screening

Author

Itoh, Hideki, primary, Crotti, Lia, additional, Aiba, Takeshi, additional, Spazzolini, Carla, additional, Denjoy, Isabelle, additional, Fressart, Véronique, additional, Hayashi, Kenshi, additional, Nakajima, Tadashi, additional, Ohno, Seiko, additional, Makiyama, Takeru, additional, Wu, Jie, additional, Hasegawa, Kanae, additional, Mastantuono, Elisa, additional, Dagradi, Federica, additional, Pedrazzini, Matteo, additional, Yamagishi, Masakazu, additional, Berthet, Myriam, additional, Murakami, Yoshitaka, additional, Shimizu, Wataru, additional, Guicheney, Pascale, additional, Schwartz, Peter J., additional, and Horie, Minoru, additional

Published
2015
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17. Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Author

Itoh, Hideki, primary, Berthet, Myriam, additional, Fressart, Véronique, additional, Denjoy, Isabelle, additional, Maugenre, Svetlana, additional, Klug, Didier, additional, Mizusawa, Yuka, additional, Makiyama, Takeru, additional, Hofman, Nynke, additional, Stallmeyer, Birgit, additional, Zumhagen, Sven, additional, Shimizu, Wataru, additional, Wilde, Arthur A M, additional, Schulze-Bahr, Eric, additional, Horie, Minoru, additional, Tezenas du Montcel, Sophie, additional, and Guicheney, Pascale, additional

Published
2015
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18. Identification of a KCNQ1 Polymorphism Acting as a Protective Modifier Against Arrhythmic Risk in Long-QT Syndrome

Author

Duchatelet, Sabine, primary, Crotti, Lia, additional, Peat, Rachel A., additional, Denjoy, Isabelle, additional, Itoh, Hideki, additional, Berthet, Myriam, additional, Ohno, Seiko, additional, Fressart, Véronique, additional, Monti, Maria Cristina, additional, Crocamo, Cristina, additional, Pedrazzini, Matteo, additional, Dagradi, Federica, additional, Vicentini, Alessandro, additional, Klug, Didier, additional, Brink, Paul A., additional, Goosen, Althea, additional, Swan, Heikki, additional, Toivonen, Lauri, additional, Lahtinen, Annukka M., additional, Kontula, Kimmo, additional, Shimizu, Wataru, additional, Horie, Minoru, additional, George, Alfred L., additional, Trégouët, David-Alexandre, additional, Guicheney, Pascale, additional, and Schwartz, Peter J., additional

Published
2013
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19. 290 The KCNQ1 rs2074238 polymorphism is a genetic modifier of cardiac risk in long QT syndrome

Author

Duchatelet, Sabine, primary, Peat, Rachel, additional, Denjoy, Isabelle, additional, Itoh, Hideki, additional, Berthet, Myriam, additional, Crotti, Lia, additional, Ohno, Seiko, additional, Fressart, Véronique, additional, Pedrazzini, Matteo, additional, Klug, Didier, additional, Trégouët, David-Alexandre, additional, Schwartz, Peter J., additional, Shimizu, Wataru, additional, Horie, Minoru, additional, and Guicheney, Pascale, additional

Published
2012
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20. Response to the Letter by Kattygnarath et al

Author

Kattygnarath, Darouna, primary, Maugenre, Svetlana, additional, Neyroud, Nathalie, additional, Balse, Elise, additional, Ichai, Carole, additional, Denjoy, Isabelle, additional, Dilanian, Gilles, additional, Martins, Raphaël P., additional, Fressart, Véronique, additional, Berthet, Myriam, additional, Schott, Jean Jacques, additional, Leenhardt, Antoine, additional, Probst, Vincent, additional, Le Marec, Hervé, additional, Hainque, Bernard, additional, Coulombe, Alain, additional, Hatem, Stéphane N., additional, and Guicheney, Pascale, additional

Published
2011
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21. Heart rate influences on repolarization duration and morphology in symptomatic versus asymptomatic KCNQ1 mutation carriers

Author

Extramiana, Fabrice, primary, Denjoy, Isabelle, additional, Badilini, Fabio, additional, Chabani, Iheb, additional, Neyroud, Nathalie, additional, Berthet, Myriam, additional, Fressard, Véronique, additional, Guicheney, Pascale, additional, Beaufils, Philippe, additional, Leenhardt, Antoine, additional, Coumel, Philippe, additional, and Maison-Blanche, Pierre, additional

Published
2005
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22. Long QT syndrome in neonates

Author

Lupoglazoff, Jean-Marc, primary, Denjoy, Isabelle, additional, Villain, Elisabeth, additional, Fressart, Véronique, additional, Simon, Françoise, additional, Bozio, André, additional, Berthet, Myriam, additional, Benammar, Nawal, additional, Hainque, Bernard, additional, and Guicheney, Pascale, additional

Published
2004
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23. Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Author

Itoh, Hideki, Berthet, Myriam, Fressart, Véronique, Denjoy, Isabelle, Maugenre, Svetlana, Klug, Didier, Mizusawa, Yuka, Makiyama, Takeru, Hofman, Nynke, Stallmeyer, Birgit, Zumhagen, Sven, Shimizu, Wataru, Wilde, Arthur A M, Schulze-Bahr, Eric, Horie, Minoru, Tezenas du Montcel, Sophie, and Guicheney, Pascale

Abstract

Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.

Published
2016
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24. C-terminal HERG Mutations

Author

Berthet, Myriam, primary, Denjoy, Isabelle, additional, Donger, Claire, additional, Demay, Laurence, additional, Hammoude, Hicham, additional, Klug, Didier, additional, Schulze-Bahr, Eric, additional, Richard, Pascale, additional, Funke, Harald, additional, Schwartz, Ketty, additional, Coumel, Philippe, additional, Hainque, Bernard, additional, and Guicheney, Pascale, additional

Published
1999
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28. Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population.

Author

Gouas, Laetitia, Nicaud, Viviane, Berthet, Myriam, Forhan, Anne, Tiret, Laurence, Balkau, Beverley, and Guicheney, Pascale

Subjects
GENETIC polymorphisms, POPULATION genetics, ION channels, GENETICS, ACTIVE biological transport, ION-permeable membranes, CARDIOVASCULAR diseases
Abstract

The QT interval (QT) reflects cardiac ventricular repolarization and varies according to various known factors such as heart rate, gender and age. Nevertheless, a high intrasubject stability of the QT-RR pattern also suggests that a genetic component contributes to individual QT length. To determine whether single nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels were associated with the heart-rate corrected QT (QTc) length, we analyzed two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2008 healthy subjects. A total of 17 polymorphisms were genotyped; they were all in the Hardy–Weinberg equilibrium in both groups. Neither allele nor haplotype frequencies of the 10 KCNQ1 SNPs showed a significant difference between the two groups. In contrast, KCNH2 2690 C (K897T) and SCN5A 5457 T (D1819D) minor alleles were significantly more frequent in the group with the shortest QTc interval, whereas KCNE1 253 A (D85N), SCN5A 1673 G (H558R) and 1141-3 A minor alleles were significantly more frequent in the group with the longest QTc interval. Interestingly, an interaction was also found between the KCNH2 2690 A>C SNP and the KCNQ1 2031+932 A>G SNP suggesting that the effect of the KCNH2 2690 C allele on QTc length may occur within a particular genetic background. This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases.European Journal of Human Genetics (2005) 13, 1213–1222. doi:10.1038/sj.ejhg.5201489; published online 31 August 2005 [ABSTRACT FROM AUTHOR]

Published
2005
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29. New KCNQ1 mutations leading to haploinsufficiency in a general population: Defective trafficking of a KvLQT1 mutant

Author

Gouas, Laetitia, Bellocq, Chloe, Berthet, Myriam, Potet, Franck, Demolombe, Sophie, Forhan, Anne, Lescasse, Rachel, Simon, Françoise, Balkau, Beverley, Denjoy, Isabelle, Hainque, Bernard, Baró, Isabelle, and Guicheney, Pascale

Subjects
HEART diseases, MEMBRANE proteins, HYPOGLYCEMIC agents, POLYMERASE chain reaction, CELL membranes
Abstract

Objective: KCNQ1 mutations lead to the long QT syndrome (LQTS), characterized by a prolonged QT interval, syncopes and sudden death. However, some mutations are associated with non-penetrant phenotype (no symptoms, QTc normal or borderline). The objective of this study was to determine whether KCNQ1 variants are associated with borderline QTc prolongation in a general population and to evaluate the frequency of carriers. Methods: We selected 2008 unrelated and untreated healthy individuals from a non-patient population. The KCNQ1 gene was screened by denaturing high-performance liquid chromatography (dHPLC) in 50 men and 50 women presenting the longest QTc intervals (403 to 443 ms). Results: We identified a nonsense mutation, Y148X, and an in-frame deletion of the serine residue 276 (ΔS276), in S2 and S5 transmembrane domains, respectively. ΔS276 KvLQT1 channels expressed in COS-7 cells failed to conduct any K+ current in the homozygous state. Besides, a slight reduction in channel activity was observed when coexpressed with WT KvLQT1 and IsK. Confocal microscopy performed on transfected COS-7 cells revealed that ΔS276 KvLQT1 was retained in the endoplasmic reticulum, whereas WT KvLQT1 was localized in the cell membrane. The two mutation carriers presented borderline QTc interval prolongation at slow heart rate but a 24-h ECG recording revealed a marked QTc prolongation at higher heart rate for the Y148X carrier. Conclusions: In this population, two subjects with borderline QTc prolongations (438 and 443 ms) were carriers of KCNQ1 mutations leading to haploinsufficiency and are potentially at risk of developing drug-induced arrhythmia. The study provides the first demonstration of a defective cell surface localization of a KvLQT1 mutant missing one amino acid in a transmembrane domain. [Copyright &y& Elsevier]

Published
2004
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30. Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes.

Author

Deschênes, Isabelle, Baroudi, Ghayath, Berthet, Myriam, Barde, Isabelle, Chalvidan, Thierry, Denjoy, Isabelle, Guicheney, Pascale, and Chahine, Mohamed

Abstract

Familial long QT syndrome (LQTS) and Brugada syndrome are two distinct human hereditary cardiac diseases known to cause ventricular tachyarrhythmias (torsade de pointes) and idiopathic ventricular fibrillation, respectively, which can both lead to sudden death. Objective: In this study we have identified and electrophysiologically characterized, in patients having either LQTS or Brugada syndrome, three mutations in SCN5A (a cardiac sodium channel gene). Method: The mutant channels were expressed in a mammalian expression system and studied by means of the patch clamp technique. Results: The R1512W mutation found in our first patient diagnosed with Brugada syndrome produced a slowing of both inactivation and recovery from inactivation. The R4132G mutation found in our second patient who also presented Brugada syndrome, resulted in no measurable sodium currents. Both Brugada syndrome patients showed ST segment elevation and right bundle-branch block, and had experienced syncopes. The E1784K mutation found in the LQTS showed a persistent inward sodium current, a hyperpolarized shift of the steady-sate inactivation and a faster recovery from inactivation. Conclusion: The different clinical manifestations of these three mutations most probably originate from the distinct electrophysiological abnormalities of the mutant cardiac sodium channels reported in this study. [ABSTRACT FROM PUBLISHER]

Published
2000

31. Identification of a KCNQ1Polymorphism Acting as a Protective Modifier Against Arrhythmic Risk in Long-QT Syndrome

Author

Duchatelet, Sabine, Crotti, Lia, Peat, Rachel A., Denjoy, Isabelle, Itoh, Hideki, Berthet, Myriam, Ohno, Seiko, Fressart, Véronique, Monti, Maria Cristina, Crocamo, Cristina, Pedrazzini, Matteo, Dagradi, Federica, Vicentini, Alessandro, Klug, Didier, Brink, Paul A., Goosen, Althea, Swan, Heikki, Toivonen, Lauri, Lahtinen, Annukka M., Kontula, Kimmo, Shimizu, Wataru, Horie, Minoru, George, Alfred L., Trégouët, David-Alexandre, Guicheney, Pascale, and Schwartz, Peter J.

Abstract

Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.

Published
2013
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32. Long QT syndrome in neonates Conduction disorders associated with HERGmutations and sinus bradycardia with KCNQ1mutations

Author

Lupoglazoff, Jean-Marc, Denjoy, Isabelle, Villain, Elisabeth, Fressart, Véronique, Simon, Françoise, Bozio, André, Berthet, Myriam, Benammar, Nawal, Hainque, Bernard, and Guicheney, Pascale

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, cardiovascular system, cardiovascular diseases
Abstract

ObjectivesWe hypothesized that neonatal long QT syndrome (LQTS) with 2:1 atrioventricular block (AVB) could be related to HERGmutations.BackgroundEarly onset of LQTS is rare but carries a high risk of life-threatening events such as ventricular arrhythmias and conduction disorders. There are no data on possible gene specificity.MethodsWe analyzed the characteristics and outcomes of 23 neonate probands from our LQTS population. Samples of DNA were available in 18 cases.ResultsLong QT syndrome was diagnosed because of corrected QT interval (QTc) prolongation (mean QTc of 558 ± 62 ms) and neonatal bradycardia attributable to sinus bradycardia (n = 8) or 2:1 AVB (n = 15). Symptoms included syncope (n = 2), torsades de pointes (n = 7), and hemodynamic failure (n = 6). Three infants with 2:1 AVB died during the first month of life. During the neonatal period, all living patients received beta-blockers (BB) and 13 had a combination of BB and permanent cardiac pacing. Under treatment, patients remained asymptomatic, with a mean follow-up of seven years. Mutations were identified in HERG(n = 8) and KCNQ1(n = 8), and one child had three mutations (HERG, KCNQ1, and SCN5A). Conduction disorders were associated with LQT2, whereas sinus bradycardia was associated with LQT1.ConclusionsTwo-to-one AVB seems preferentially associated with HERGmutations, either isolated or combined. Long QT syndrome with relative bradycardia attributable to 2:1 AVB has a poor prognosis during the first month of life. In contrast, sinus bradycardia seems to be associated with KCNQ1mutations, with a good short-term prognosis under BB therapy.

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33. A mutation in HERG Associated with Notched T waves in Long QT Syndrome

Author

Dausse, Eric, Berthet, Myriam, Denjoy, Isabelle, Andre´-Fouet, Xavier, Cruaud, Corrine, Bennaceur, Mohammed, Faure´, Sabine, Coumel, Philippe, Schwartz, Ketty, and Guicheney, Pascale

Abstract

Long QT syndrome (LQT) is a genetically heterogeneous inherited disorder that causes sudden death from cardiac arrhythmia. Four loci have been mapped to chromosomes 3, 4, 7 and 11 and three specific mutated genes for LQT syndrome have been identified. LQT2 results from mutations in the human ether-a-gogo-related gene, HERG, a cardiac potassium channel, whose protein product likely underlies IKr, the rapidly activating delayed rectifier current. By SSCP analysis and direct sequencing, we determined a new missense mutation in the HERG coding sequence, a G to A transition at position 1681 resulting in the substitution of threonine for a highly conserved alanine at codon 561. This mutation, Ala561Thr, in the coding sequence of the fifth membrane-spanning domain (S5) of the HERG protein seems to convey a risk of cardiac events in affected family members. In addition to a prolonged T wave of low amplitude on the surface ECG, a distinctive biphasic T-wave pattern was found in the left precordial leads of all affected subjects with the Ala561Thr mutation regardless of age, gender and beta blocking therapy.

Published
1996
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34. MOG1: a new susceptibility gene for Brugada syndrome.

Author

Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C, Denjoy I, Dilanian G, Martins RP, Fressart V, Berthet M, Schott JJ, Leenhardt A, Probst V, Le Marec H, Hainque B, Coulombe A, Hatem SN, and Guicheney P

Subjects
Amino Acid Sequence, Animals, DNA Mutational Analysis, Electrocardiography, Female, HEK293 Cells, Humans, Molecular Sequence Data, Myocytes, Cardiac cytology, Myocytes, Cardiac physiology, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Rats, Rats, Wistar, Sequence Alignment, Sodium Channels genetics, Transfection, Brugada Syndrome genetics, Genetic Predisposition to Disease, ran GTP-Binding Protein genetics
Abstract

Background: Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS., Methods and Results: MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation. A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)- and mutant E83D-MOG1 were expressed in HEK Na(v)1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I(Na)) density compared to control conditions (P<0.01). In contrast, overexpression of mutant E83D alone or E83D+WT failed to increase I(Na) (P<0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na(v)1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I(Na) density., Conclusions: Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na(v)1.5 to the membrane, leading to I(Na) reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I(Na), demonstrating that MOG1 is likely to be important in the surface expression of Na(v)1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS.

Published
2011
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