title: A heterozygous deletion mutation in the cardiac sodium channel gene SCN5A with loss- and gain-of-function characteristics manifests as isolated conduction disease, without signs of Brugada or long QT syndrome.
abstract: BACKGROUND
  The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome.
  
  
  RESULTS
  In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation).
  
  
  CONCLUSIONS
  In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.
authors.affiliation: Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany. Sven.Zumhagen@ukmuenster.de
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.forename: Antonius
authors.initials: A
authors.lastname: Baartscheer
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
authors.forename: Matthias
authors.initials: M
authors.lastname: Paul
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
mesh_terms: D000200:Action Potentials / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075224:Cardiac Conduction System Disease; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000473:pathology; D004562:Electrocardiography / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006321:Heart / Q000503:physiopathology; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium