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.

中文翻译：

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Andersen Tawil 综合征致心律失常机制的分子分层

Andersen Tawil 综合征 (ATS) 是一种罕见的遗传性疾病，与 KCNJ2 中的功能丧失突变有关，该基因编码强内向整流钾通道 Kir2.1，形成控制心脏兴奋性的必需膜蛋白。ATS 通常以周期性麻痹、危及生命的心律失常和畸形特征三联征为标志，但其表达是可变的，并非所有具有与 ATS 相关表型的患者都具有已知的基因改变。这种致心律失常综合征的潜在机制知之甚少。了解这些机制对于将 ATS 与具有重叠表型的其他离子通道病区分开来以及开发个体化疗法至关重要。例如，最近建议的 Kir2 角色。1 作为肌浆钙再摄取的逆流可能解释了 ATS 的致心律失常机制及其与儿茶酚胺能多形性室性心动过速 (CPVT) 的重叠。在这里，我们总结了目前关于 ATS 中导致心源性猝死的心律失常机制的知识。我们首先概述了该综合征及其病理生理学，从患者的床边到蛋白质，并讨论了可能在 ATS 病例中发挥作用的基本调节剂和相互作用物的作用。该综述重点介绍了与一些翻译后通道与伴侣蛋白相互作用相关的新想法，这些相互作用可能有助于定义心律失常表型的分子基础。然后，我们根据它们在 Kir2 中的位置，对目前已知的 ATS 功能丧失突变提出了一个新的包罗万象的分类。1 渠道结构及其功能含义。我们还讨论了特定的 ATS 致病变异、它们的临床表现和治疗分层。目标是为开发新靶点和个性化治疗策略提供对该综合征更深入的机制理解。