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J Mol Cell Cardiol. 2005 Jun;38(6):969-81. Epub 2005 Apr 1.

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.

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Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, The Netherlands.



Mutations in the gene encoding the human cardiac sodium channel (SCN5A) have been associated with three distinct cardiac arrhythmia disorders: the long QT syndrome, the Brugada syndrome and cardiac conduction disease. Here we report the biophysical features of a novel sodium channel mutation, E161K, which we identified in individuals of two non-related families with symptoms of bradycardia, sinus node dysfunction, generalized conduction disease and Brugada syndrome, or combinations thereof.


Wild-type (WT) or E161K sodium channel alpha-subunit and beta-subunit were cotransfected into tsA201 cells to study the functional consequences of mutant sodium channels. Characterization of whole-cell sodium current (I(Na)) using the whole cell patch-clamp technique revealed that the E161K mutation caused an almost threefold reduction in current density (P < 0.001), and an 11.9 mV positive shift of the voltage-dependence of activation (P < 0.0001). The inactivation properties of mutant and WT sodium channels were similar. These results suggest an overall reduction of E161K I(Na). Incorporation of the experimental findings into computational models demonstrate atrial and ventricular conduction slowing as well as a reduction in sinus rate by slowing of the diastolic depolarization rate and upstroke velocity of the sinus node action potential. This reduction in sinus rate was aggravated by application of acetylcholine, simulating the dominant vagal tone during night.


Our experimental and computational analysis of the E161K mutation suggests that a loss of sodium channel function is not only associated with Brugada syndrome and conduction disease, but may also cause sinus node dysfunction in carriers of this mutation.

[Indexed for MEDLINE]

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