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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.

AbstractBACKGROUND:
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.
METHOD AND 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).
CONCLUSION:
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.
AuthorsSven Zumhagen, Marieke W Veldkamp, Birgit Stallmeyer, Antonius Baartscheer, Lars Eckardt, Matthias Paul, Carol Ann Remme, Zahurul A Bhuiyan, Connie R Bezzina, Eric Schulze-Bahr
JournalPloS one (PLoS One) Vol. 8 Issue 6 Pg. e67963 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23840796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels
  • Sodium
Topics
  • Action Potentials (genetics)
  • Arrhythmias, Cardiac (genetics, metabolism, pathology)
  • Brugada Syndrome (genetics, metabolism, pathology)
  • Cardiac Conduction System Disease
  • Cell Line
  • Death, Sudden, Cardiac (pathology)
  • Electrocardiography (methods)
  • Female
  • HEK293 Cells
  • Heart (physiopathology)
  • Heart Conduction System (abnormalities, metabolism, pathology)
  • Heterozygote
  • Humans
  • Long QT Syndrome (genetics, metabolism, pathology)
  • Male
  • Middle Aged
  • NAV1.5 Voltage-Gated Sodium Channel (genetics, metabolism)
  • Pedigree
  • Sarcolemma (genetics, metabolism, pathology)
  • Sequence Deletion (genetics)
  • Sodium (metabolism)
  • Sodium Channels (genetics, metabolism)

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