title: Gain-of-function mutation of the SCN5A gene causes exercise-induced polymorphic ventricular arrhythmias.
abstract: BACKGROUND
  Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family.
  
  
  RESULTS
  A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Nav1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells.
  
  
  CONCLUSIONS
  Gain-of-function of Nav1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland. heikki.swan@helsinki.fi.
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Mohamed Yassine
authors.initials: MY
authors.lastname: Amarouch
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Leinonen
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Annukka
authors.initials: A
authors.lastname: Marjamaa
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kucera
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Laitinen-Forsblom
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.affiliation: From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widen
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac; D005080:Exercise Test; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011689:Purkinje Cells / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000000981:diagnostic imaging / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: SCN5A; arrhythmia (heart rhythm disorders); catecholaminergic polymorphic ventricular tachycardia; exercise test; genetic testing; mutation