期刊
PLOS ONE
卷 8, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0067963
关键词
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资金
- Fondation Leducq, Paris, France
- German Research Foundation, Bonn, Germany (DFG) [SFB 656-C1]
- Interdisciplinary Center for Clinical Research, Munster, Germany (IZKF) [Schu01-012-11]
- Innovative medicine research, Munster, Germany (IMF) [ST121119]
Background: The SCN5A gene encodes for the alpha-subunit of the cardiac sodium channel Na(V)1.5, 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 degrees 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.
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