Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.
Mutations in multiple genes have been implicated in familial atrial fibrillation (AF), but the underlying mechanisms, and thus implications for therapy, remain ill-defined. Among 231 participants in the Vanderbilt AF Registry, we found a mutation in KCNQ1 (encoding the alpha-subunit of slow delayed rectifier potassium current [I(Ks)]) and separately a mutation in natriuretic peptide precursor A (NPPA) gene (encoding atrial natriuretic peptide, ANP), both segregating with early onset lone AF in different kindreds. The functional effects of these mutations yielded strikingly similar I(Ks) "gain-of-function." In Chinese Hamster Ovary (CHO) cells, coexpression of mutant KCNQ1 with its ancillary subunit KCNE1 generated approximately 3-fold larger currents that activated much faster than wild-type (WT)-I(Ks). Application of the WT NPPA peptide fragment produced similar changes in WT-I(Ks), and these were exaggerated with the mutant NPPA S64R peptide fragment. Anantin, a competitive ANP receptor antagonist, completely inhibited the changes in I(Ks) gating observed with NPPA S64R. Computational simulations identified accelerated transitions into open states as the mechanism for variant I(Ks) gating. Incorporating these I(Ks) changes into computed human atrial action potentials (AP) resulted in 37% shortening (120 vs. 192 ms at 300 ms cycle length), reflecting loss of the phase II dome which is dependent on L-type calcium channel current. We found striking functional similarities due to mutations in KCNQ1 and NPPA genes which led to I(Ks) "gain-of-function", atrial AP shortening, and consequently altered calcium current as a common mechanism between diverse familial AF syndromes.
Abraham
Robert L
RL
Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 1285A MRB IV, 2311 Pierce Avenue, Nashville, TN 37232-6602, USA.
Yang
Tao
T
Blair
Marcia
M
Roden
Dan M
DM
Darbar
Dawood
D
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000328:Adult; D001281:Atrial Fibrillation / Q000235:genetics*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D003198:Computer Simulation; D004594:Electrophysiology; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011188:Potassium / Q000378:metabolism*
D051657:KCNQ1 Potassium Channel; C472955:NPPA protein, human; D009320:Atrial Natriuretic Factor; D011188:Potassium