title: Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms.
abstract: BACKGROUND
  Congenital atrial standstill has been linked to SCN5A. Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of polymorphisms in the atrial-specific gap junction connexin 40 (Cx40) in conjunction with an SCN5A mutation.
  
  
  OBJECTIVE
  The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill.
  
  
  METHODS
  Family members of an apparently sporadic case of atrial standstill underwent genetic screening of SCN5A and atrial-specific genes including Cx40. Biophysical properties of the wild-type (WT) and mutant SCN5A channels in a heterologous expression system were studied using the whole-cell patch clamp technique.
  
  
  RESULTS
  The novel SCN5A mutation L212P was identified in the proband (age 11 years) and his father. The father was in normal sinus rhythm. The proband had no P waves on surface ECG, and his right atrium could not be captured by pacing. The recombinant L212P Na channel showed a large hyperpolarizing shift in both the voltage dependence of activation (WT: -48.1 +/- 0.9 mV; L212P: -63.5 +/- 1.5 mV; P < .001) and inactivation (WT: -86.6 +/- 0.9 mV; L212P: -95.6 +/- 0.8 mV; P < .001) and delayed recovery from inactivation. Further screenings for genetic variations that might mitigate L212P dysfunction revealed that the proband, but not his father, carries Cx40 polymorphisms inherited from his asymptomatic mother.
  
  
  CONCLUSIONS
  These results suggest that genetic defects in SCN5A most likely underlie atrial standstill. Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. makitan@med.hokudai.ac.jp
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Koji
authors.initials: K
authors.lastname: Sasaki
authors.forename: W Antoinette
authors.initials: WA
authors.lastname: Groenewegen
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yokoshiki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Murakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000483:Alleles; D001281:Atrial Fibrillation / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D016275:Atrial Function / Q000235:genetics; D001919:Bradycardia / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D002675:Child, Preschool; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels; D000097003:Gap Junction alpha-5 Protein; C568320:SCN5A protein, human