ArticleCirculation research2014
Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome.
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33 citing papers in PubMed, 60 citations in OpenAlex.
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- Aortic disease and cardiomyopathy in patients with a novel DNMT3A gene variant causing Tatton-Brown-Rahman syndrome.Clinical epigenetics · 2024Article
- Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.JCI insight · 2023Article
- Brugada Syndrome: More than a Monogenic Channelopathy.Biomedicines · 2023Review
- Concealed Substrates in Brugada Syndrome: Isolated Channelopathy or Associated Cardiomyopathy?Genes · 2022Review
- J wave syndromes: What's new?Trends in cardiovascular medicine · 2022Review
- Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction.Circulation · 2022Article
- SEMAPHORINS and their receptors: focus on the crosstalk between melanoma and hypoxia.Journal of experimental & clinical cancer research : CR · 2021Review
- Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.International journal of molecular sciences · 2021Review
- Kallmann syndrome and idiopathic hypogonadotropic hypogonadism: The role of semaphorin signaling on GnRH neurons.Handbook of clinical neurology · 2021Review
- Brugada Syndrome: Oligogenic or Mendelian Disease?International journal of molecular sciences · 2020Review
- Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies.International journal of cardiology. Heart & vasculature · 2020Review
- Recognizable type of pituitary, heart, kidney and skeletal dysplasia mostly caused byWorld journal of clinical cases · 2019Article
- Mechanisms Underlying the Actions of Antidepressant and Antipsychotic Drugs That Cause Sudden Cardiac Arrest.Arrhythmia & electrophysiology review · 2018Review
- J wave syndromes as a cause of malignant cardiac arrhythmias.Pacing and clinical electrophysiology : PACE · 2018Review
- Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes.International journal of legal medicine · 2018Article
- Recent advances in the treatment of Brugada syndrome.Expert review of cardiovascular therapy · 2018Review
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Authors and funding
15 authors at 5 institutions in 3 countries.
Nicole J BoczekFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Dan YeFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Eric K JohnsonFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Wei WangFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Lia CrottiFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
David J TesterFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Federica DagradiFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Yuka MizusawaFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Margherita TorchioFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Marielle AldersFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
John R GiudicessiFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Arthur A M WildeFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Peter J SchwartzFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Jeanne M NerbonneFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.).
Michael J AckermanFrom the Center for Clinical and Translational Science (N.J.B.) and Mayo Graduate School (N.J.B.), Department Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (D.Y., D.J.T., J.R.G., M.J.A.), Department of Medicine (J.R.G.), Division of Cardiovascular Diseases (M.J.A.), and Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO (E.K.J., W.W., J.M.N.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., F.D., M.T., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany (L.C.); and Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (Y.M., M.A., A.A.M.W.). ackerman.michael@mayo.edu.
University of Pavia · ITHelmholtz Zentrum München · DEIRCCS Istituto Auxologico Italiano · ITIstituti di Ricovero e Cura a Carattere Scientifico · ITWashington University in St. Louis · US
Funding
Mayo Clinic Center for Translational Science ActivitiesUL1TR000135 · NCATS · MAYO CLINIC ROCHESTER · PI KHOSLA, SUNDEEP · 2012 to 2015
$41.2MCardiac Channel Mutations in Sudden Infant Death Syndrome (SIDS)R01HD042569 · NICHD · MAYO CLINIC ROCHESTER · PI ACKERMAN, MICHAEL JOHN · 2002 to 2017
$6.9MNCATS NIH HHS UL1 TR000135NICHD NIH HHS R01 HD042569
Abstract
rationaleSemaphorin 3A (SEMA3A)-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K(+) channels. SEMA3A-knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death.
objectiveOur aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of Kv4.3 (Ito) channels and its potential contribution to Brugada syndrome. METHODS AND
resultsKv4.3, Nav1.5, Cav1.2, or Kv4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered Kv4.3 by significantly reducing peak current density without perturbing Kv4.3 cell surface protein expression. SEMA3A also reduced Ito current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on Kv4.3 was used to assess physical interactions between SEMA3A and Kv4.3. These findings in combination with coimmunoprecipitations of SEMA3A and Kv4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype-negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A's ability to inhibit Kv4.3 channels, resulting in a significant gain of Kv4.3 current compared with wild-type SEMA3A.
conclusionsThis study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits Kv4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a Kv4.3 gain-of-function mechanism.
Indexed as
AdultBrugada SyndromeDNA Mutational AnalysisDose-Response Relationship, DrugElectrocardiographyFemaleGenetic Predisposition to DiseaseHEK293 CellsHumansImmunoprecipitationKineticsMaleMembrane PotentialsMiddle AgedMutation, MissenseMyocytes, CardiacKCND3 protein, humanPotassium Channel BlockersSEMA3A protein, humanSemaphorin-3AShal Potassium ChannelsBrugada syndromegenetics, medicalion channelspotassium channelssemaphorin-3A
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