title: A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation.
abstract: BACKGROUND
  Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias.
  
  
  OBJECTIVE
  To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block.
  
  
  METHODS
  Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels.
  
  
  RESULTS
  The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential.
  
  
  CONCLUSIONS
  We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Azza
authors.initials: A
authors.lastname: Ziyadeh-Isleem
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.|Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clatot
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Duchatelet
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Département de Cardiologie, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.|AP-HP, Hôpital Bichat, Département de Cardiologie, Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Département de Cardiologie, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Hidden-Lucet
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hatem
authors.affiliation: Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschênes
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Coulombe
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neyroud
authors.affiliation: INSERM, UMR_S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001281:Atrial Fibrillation / Q000235:genetics*; D002478:Cells, Cultured; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012804:Sick Sinus Syndrome / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: Arrhythmia; Atrial fibrillation; Na(v)1.5; PITX2; Polymorphism; SCN5A; SNP; Sodium