Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome

Abstract

Andersen Tawil Syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient´s bedside to the protein, and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3

“…This might be due to sodium inward current (I Na ) modification induced by the Kir2.1 E299V mutation. 21 , 34 In an additional group of experiments, we measured I Na in atrial and ventricular cardiomyocytes. In Figure 7 A superimposed IV relations (Ai), and activation and inactivation curves (Aii) from Kir2.1 WT and Kir2.1 E299V atrial cardiomyocytes showed that the mutation did not modify either I Na density or its biophysical properties (Aiii and Aiv).…”

“… 20 Trafficking-deficient mutations in one of these channels reduce the surface expression and current density of the other. 21–25 However, it is unknown whether gain-of-function mutations in one or the other channel modify such interactions or result in unforeseen electrical remodelling mediated by changes in other interacting proteins.…”

Extracellular Kir2.1 C122Y Mutant Upsets Kir2.1-PIP 2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome

“…Defects in PIP 2 binding are a major pathophysiologic mechanism underlying the loss-of-function phenotype for several ATS1-associated mutations. 5,9–11…”

“…1,2 Kir2.1 is ubiquitously expressed throughout the human body, and ATS1 mutations predispose patients to a triad of alterations including periodic paralysis, dysmorphias, and arrhythmias that can lead to sudden cardiac death 3,4 by mechanisms that remain unclear. 5 In the heart, Kir2.1 is responsible for the inward rectifier K + current (I K1 ), 6 which plays a central role in the maintenance of the resting membrane potential (RMP) and the final phase of action potential (AP) repolarization. 7 Therefore, loss-of-function mutations in Kir2.1 lead to a substantial decrease in I K1 , with consequent membrane depolarization at rest, as well as AP duration and corrected QT (QTc) interval prolongation.…”

“…Defects in PIP 2 binding are a major pathophysiologic mechanism underlying the loss-of-function phenotype for several ATS1-associated mutations. 5,[9][10][11] The primary structure of the human Kir2.1 channel comprises a total of 13 Cys (cysteine) residues distributed along each monomer. Cys residues are uniquely reactive providing the ability to form disulfide bonds.…”