PubMed 22685113

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNQ1 , Kv7.1 , Nav1.5

Title: High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation.

Authors: Morten S Olesen, Lei Yuan, Bo Liang, Anders G Holst, Nikolaj Nielsen, Jonas B Nielsen, Paula L Hedley, Michael Christiansen, Søren-Peter Olesen, Stig Haunsø, Nicole Schmitt, Thomas Jespersen, Jesper H Svendsen

Journal, date & volume: Circ Cardiovasc Genet, 2012 Aug 1 , 5, 450-9

PubMed link:

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A.The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current.In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.