Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility
Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2)...
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| Published in | Circulation. Cardiovascular genetics Vol. 7; no. 4; pp. 466 - 474 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.08.2014
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.
We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT. |
|---|---|
| AbstractList | Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.
We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT. Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.BACKGROUNDGenetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.METHODS AND RESULTSWe used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.CONCLUSIONSCALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT. |
| Author | George, Alfred L. Lichtner, Peter Theisen, Daniel Klug, Didier Chazin, Walter J. Shimizu, Wataru Makita, Naomasa Johnson, Christopher N. Meitinger, Thomas Yagihara, Nobue Ozaki, Kouichi Guicheney, Pascale Beckmann, Britt-Maria Bhuiyan, Zahurul A. Crotti, Lia Endo, Naoto Tsunoda, Tatsuhiko Toda, Tatsushi Aiba, Takeshi Watanabe, Hiroshi Behr, Elijah R. Denjoy, Isabelle Miyamoto, Yoshihiro Suda, Kenji Tsuchiya, Takeshi Motomura, Hideki Satake, Wataru Nakagawa, Hidewaki Roh, Michelle S. Shigemizu, Daichi Schwartz, Peter J. Homfray, Tessa Mastantuono, Elisa Ishikawa, Taisuke Tanaka, Toshihiro Tsuji, Yukiomi Kimura, Akinori Yamamoto, Hirokazu Kääb, Stefan |
| AuthorAffiliation | 5 Department of Biochemistry, the Center for Structural Biology, Vanderbilt University, Nashville, TN 9 Department of Genetics, St. George’s University of London, London, United Kingdom 10 Cardiovascular Sciences Research Centre, St. George’s University of London, London, United Kingdom 12 Inserm, UMR_S1166, Institute of Cardiometabolism and Nutrition, ICAN 6 Department of Medicine I, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany 11 Hôpital Cardiologique de Lille, Service de Cardiologie, Lille 7 Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 20 Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 8 Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan 4 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany 31 Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 28 Sor |
| AuthorAffiliation_xml | – name: 29 Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan – name: 24 Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan – name: 18 Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki – name: 22 Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan – name: 16 Laboratory for Genome Sequencing Analysis, St. George’s University of London, London, United Kingdom – name: 14 Institute for Clinical Radiology, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Munich, Grosshadern, Germany – name: 30 Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland – name: 23 Department of Pediatrics and Child Health Cardiovascular Research Institute, Kurume University School of Medicine, Kurume – name: 8 Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan – name: 25 IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy – name: 19 Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan – name: 10 Cardiovascular Sciences Research Centre, St. George’s University of London, London, United Kingdom – name: 4 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany – name: 12 Inserm, UMR_S1166, Institute of Cardiometabolism and Nutrition, ICAN – name: 1 Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki – name: 6 Department of Medicine I, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany – name: 15 Department of Neurology, Kobe University Graduate School of Medicine, Kobe – name: 3 Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy – name: 7 Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama – name: 20 Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata – name: 28 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition, Paris, France – name: 27 Institute of Human Genetics, Technische Universität München, Munich, Germany – name: 13 AP-HP, Service de Cardiologie, Hôpital Bichat, and Centre de référence sur les maladies cardiaques héréditaires, Paris, France – name: 5 Department of Biochemistry, the Center for Structural Biology, Vanderbilt University, Nashville, TN – name: 9 Department of Genetics, St. George’s University of London, London, United Kingdom – name: 2 Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan – name: 11 Hôpital Cardiologique de Lille, Service de Cardiologie, Lille – name: 21 Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo – name: 17 EP Expert Doctors-Team Tsuchiya, Kumamoto – name: 31 Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN – name: 26 Deutsches Zentrum für Herz-Kreislauf-Forschung, Munich Heart Alliance |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24917665$$D View this record in MEDLINE/PubMed |
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| Copyright | 2014 American Heart Association, Inc. |
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| SubjectTerms | Adrenergic beta-Antagonists - therapeutic use Adult Age of Onset Amino Acid Sequence Calcium - chemistry Calcium - metabolism Calmodulin - genetics Calmodulin - metabolism Child Child, Preschool Electrocardiography Female Genetic Predisposition to Disease High-Throughput Nucleotide Sequencing Humans Infant Long QT Syndrome - drug therapy Long QT Syndrome - genetics Long QT Syndrome - pathology Male Molecular Sequence Data Mutation, Missense Pedigree Protein Binding Sequence Analysis, DNA Tachycardia, Ventricular - drug therapy Tachycardia, Ventricular - genetics Tachycardia, Ventricular - pathology |
| Title | Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility |
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