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. 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.
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Authors | Sven Zumhagen, Marieke W Veldkamp, Birgit Stallmeyer, Antonius Baartscheer, Lars Eckardt, Matthias Paul, Carol Ann Remme, Zahurul A Bhuiyan, Connie R Bezzina, Eric Schulze-Bahr |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 6
Pg. e67963
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23840796
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NAV1.5 Voltage-Gated Sodium Channel
- SCN5A protein, human
- Sodium Channels
- Sodium
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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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