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.

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Introduction: Andersen-Tawil syndrome type 1 (ATS1) is associated with fatal cardiac arrhythmias. However, the underlying mechanisms are poorly understood. Hypothesis: Cardiac-specific expression of trafficking deficient Kir2.1 channels in mice in-vivo recapitulates the cardiac electrical phenotype of ATS1 and investigate the underlying mechanisms. Methods: We generated a new mouse model of ATS1 by a single i.v. injection of cardiac specific adeno-associated viral (AAV) transduction with Kir2.1 Δ314-315 , which recapitulated the ATS1 ECG phenotype without modifying ventricular function. The animal and cellular, structural and functional analyses were carried out by ECG, intracardiac stimulation, patch-clamping, membrane fractionation, western blot, immunolocalization and live calcium imaging. Results: AAV-Kir2.1 Δ314-315 mice were significantly more sensitive to flecainide than control, increasing the PR and QRS intervals over time. Kir2.1 Δ314-315 mice had increased vulnerability to cardiac fibrillation. Patch-clamping in ventricular cardiomyocytes from Kir2.1 Δ314-315 mice demonstrated significantly reduced I K1 and I Na , depolarized resting membrane potential and prolonged action potential. Immunolocalization in control mice revealed two bands of Kir2.1 staining, one colocalizing with Na V 1.5 and AP1 near the Z disk, the other near the H zone. Membrane fractionation and western blot experiments demonstrated two distinct levels of Kir2.1 protein expression, one at the sarcolemmal fraction together with Na V 1.5 and the other at the sarcoplasmi creticulum (SR). Kir2.1 Δ314-315 cardiomyocytes showed disruption of the Kir2.1-Nav1.5 channelosome at the sarcolemma, indicating dysfunctional trafficking o fboth channels. In addition, the SR Kir2.1 was disrupted and calcium transient dynamics were altered, resulting in frequent abnormal spontaneous calcium release events, and revealing an excitation-contraction coupling defect. Conclusions: Cardiac-specific AAV transduction with Kir2.1 Δ314-315 in mice recapitulates the ATS1 phenotype by disrupting localization and function of Kir2.1at the SR, and the Kir2.1-Na V 1.5 channelosome at the sarcolemma, revealing anovel dual mechanism of arrhythmogenesis.

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