Nocturnal Atrial Fibrillation Caused by KCND2 Gain of Function Variant Affecting the Circadian Rhythm-Controlled Cardiac Kv4.2 Potassium Channel

Max Drabkin ¹ Noam Zilberberg ² Sasson Menahem ³ Wesam Mulla ^1,4 Daniel Halperin ¹ Yuval Yogev ¹ Ohad Wormser ¹ Yonatan Perez ¹ Rotem Kadir ¹ Yoram Etzion ⁴ Amos Katz ^5,7 Ohad S. Birk ^1,6,7

¹The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel
²Department of Life Sciences and the Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Israel
³Department of Family Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁴Department of Physiology and Cell Biology, Faculty of Health Sciences and Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Israel
⁵Department of Cardiology, Barzilai University Medical Center, Ashkelon and Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁶Genetics Institute, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁷Note, equal contribution

Purpose: Paroxysmal atrial fibrillation (pAF) presents circadian variation. Molecular mechanisms underlying this variation are mostly unknown. We sought the genetic basis of dominantly inherited nocturnal atrial fibrillation.

Methods: Human genetic studies, Xenopus oocytes electrophysiological experiments.

Results: In affected kindred, autosomal dominant early-onset nocturnal pAF is caused by p.S447R variant in KCND2, encoding the pore-forming (α) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, with Kv4.3, contributes to the cardiac fast transient outward K+ current, I_to. In Xenopus oocytes, the p.S447R variant increased the channel’s inactivation time constant, and affected its regulation: the variant resides in a PKC phosphorylation site, which normally attenuates Kv4.2 membrane expression. Mutant Kv4.2 exhibited impaired response to PKC, augmenting Kv4.2 membrane expression and enhancing potassium currents. The Kv4.2 variant exerted gain-of-function effect on both Kv4.2 homo-tetramers and Kv4.2-Kv4.3 hetero-tetramers. Kv4.2 expression demonstrates circadian variation, peaking daytime in murine hearts (human nighttime). This nighttime overexpression of Kv4.2, together with the mutation effect, increase I_to current, abbreviating action potential duration, creating arrhythmogenic substrate for nocturnal atrial fibrillation.

Conclusion: Gain of function mutation in Kv4.2 causes nocturnal atrial fibrillation. Our data highlight the significance of personalized diurnally-variable pharmaceutical management of pAF, suggesting targeting Kv4.2 in treatment of nocturnal pAF.