Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation

Abstract

Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4-S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1-S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current I(Kur) vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

“…18 In human atrial myocytes, Kv1.5 loss-of-function mimicked by Kv1.5 blockade with 4-aminopyridine was accompanied by significant prolongation of action potential duration and associated with a predisposition to early afterdepolarization and paroxysmal oscillations in membrane potential that interrupted normal repolarization. Under the condition of adrenergic agonist administration, human atrial myocytes with Kv1.5 channel blocked were concomitant with remarkably increased triggered activity.…”

“…Specific variations in several genes associated with AF were identified and characterized. These AF-related genes are mainly as follows: KCNQ1, which encodes the a-subunit of slowly activating delayed rectifier potassium channel (IKs); 12 HERG, which encodes the a-subunit of the rapidly activating delayed rectifier potassium channel (IKr); 13 SCN5A, which encodes the a-subunit of the sodium channel; 14,15 Ankyrin-B, which encodes a member of a family of versatile membrane adapters, which is required for coordinated assembly of the Na/Ca exchanger, Na/K ATPase and inositol trisphosphate receptor at transverse tubule/sarcoplasmic reticulum sites in cardiomyocytes; 16 KCNJ2, which encodes the a-subunit of inward rectifier potassium channel (IK1); 17 KCNA5, which encodes the a-subunit of the ultrarapidly activating delayed rectifier potassium channel (Kv1.5); 18 Connexin 40, which is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria; 19 KCNE1, which encodes the b-subunit of IKs; 20 KCNE2 encoding b-subunit of IKr; 21 and KCNE3, 22 KCNE4 23 and KCNE5, 24 which encode the b-subunits of potassium channels interacting with KCNQ1, HERG and others. In addition, inheritable defects also confer substantial disease susceptibility on patients with secondary AF.…”

SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5

“…By regulating potassium ion fluxes in response to alterations of the membrane potential, Kv channels are responsible for establishing the resting membrane potential and cellular repolarization in the heart and in peripheral vascular beds (1)(2)(3). Defects in members of this class of channels are thus linked to a wide range of cardiovascular diseases (4)(5)(6). The Shaker family of Kv channels has been extensively characterized both functionally and structurally (7,8), and within this group Kv1.5 is widely represented in the cardiovascular system (9).…”

“…In the human heart Kv1.5 is selectively expressed in atrial myocytes and mediates the ultrarapid K ϩ current (I Kur ) central to action potential repolarization (10). Recently, a familial form of atrial fibrillation has been attributed to a loss-of-function mutation in Kv1.5 (6). In the pulmonary vasculature Kv1.5 plays a critical role in the oxygen-sensitive regulation of arterial tone (11).…”

A pilot study to estimate the feasibility of assessing the relationships between polymorphisms in hKv1.5 and atrial fibrillation in patients following coronary artery bypass graft surgery

“…Thus, these mutations accelerate atrial repolarization, which contributes to action potential shortening during AF. A nonsense mutation in hKv1.5 (E375X) has recently been associated with one familial case of AF (15), which demonstrates the pertinence of analyzing this potassium channel in patients suffering from AF. In addition to the hKv1.5 gene, to date, only a few other genes, KvLQT1 (16,17), Kir2.1 (18) and MiRP1 (19), have been found to be associated with AF in a very limited number of patients.…”