Referenced in: none

Automatically associated channels: Nav1.5 , Slo1

Title: A sodium-channel mutation causes isolated cardiac conduction disease.

Authors: H L Tan, M T Bink-Boelkens, C R Bezzina, P C Viswanathan, G C Beaufort-Krol, P J van Tintelen, M P van den Berg, A A Wilde, J R Balser

Journal, date & volume: Nature, 2001 Feb 22 , 409, 1043-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/11234013

Abstract
Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.