Gain of function mutation in the cardiac Kv4.2 potassium channel underlies paroxysmal atrial fibrillation

Introduction: Three generations of a kindred presented
with autosomal dominant early-onset paroxysmal atrial
fibrillation (pAF), with recurrent nocturnal self-terminating
palpitations.
Methods: Whole exome sequencing, linkage analysis,
electrophysiological assays in Xenopus oocytes.
Results: Through genetic studies we identified a diseasecausing p.S447R mutation in KCND2, encoding the poreforming (α) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, with Kv4.3, contributes to the cardiac fast
transient outward K+ current, Ito. Ito underlies the early
repolarization phase in the cardiac action potential, setting
the initial potential of the plateau phase and governing its
duration and amplitude. In Xenopus oocytes, the p.S447R
mutation increased inactivation time constant of the channel
and affected its regulation: the mutation resides in a proteinkinase C (PKC) phosphorylation site, which normally
attenuates Kv4.2 membrane expression. Mutant Kv4.2
exhibited impaired response to PKC, resulting in augmented
Kv4.2 membrane expression and enhanced potassium currents. Moreover, in a hybrid channel composed of Kv4.3
and Kv4.2, simulating the mature endogenous heterotetrameric channel underlying Ito, the Kv4.2 mutation
exerted gain-of-function effect on Kv4.3. Thus, the mutation exerts gain-of-function effect on both Kv4.2 homotetramers and Kv4.2-Kv4.3 hetero-tetramers.
Conclusions: Gain-of-function mutation in Kv4.2 causes
nocturnal pAF. Interestingly, Kv4.2 expression was previously shown to demonstrate circadian variation, with peak
expression at daytime in murine hearts (human nighttime),
with possible relevance to the nocturnal onset of paroxysmal AF symptoms in our patients. The atrial-specific
phenotype suggests that targeting Kv4.2 might be effective
in the treatment of nocturnal paroxysmal AF, avoiding
adverse ventricular effects.