Extracellular cysteine disulfide bond break at Cys122 disrupts PIP 2 -dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome.

Andersen-Tawil Syndrome Type 1 (ATS1) is a rare arrhythmogenic disease caused by loss-of-function mutations in , the gene encoding the strong inward rectifier potassium channel Kir2.1 responsible for I . Extracellular Cys and Cys form an intramolecular disulfide bond that is essential for proper Kir2.1 channel folding but not considered vital for channel function. Replacement of Cys or Cys residues in the Kir2.1 channel with either alanine or serine abolished ionic current in oocytes. We generated a mouse model that recapitulates the main cardiac electrical abnormalities of ATS1 patients carrying the C122Y mutation, including prolonged QT interval and life-threatening ventricular arrhythmias.We demonstrate for the first time that a single residue mutation causing a break in the extracellular Cys122-to-Cys154 disulfide-bond leads to Kir2.1 channel dysfunction and arrhythmias in part by reorganizing the overall Kir2.1 channel structure, disrupting PIP2-dependent Kir2.1 channel function and destabilizing the open state of the channel.Defects in Kir2.1 energetic stability alter the functional expression of the voltage-gated cardiac sodium channel Nav1.5, one of the main Kir2.1 interactors in the macromolecular channelosome complex, contributing to the arrhythmias.The data support the idea that susceptibility to arrhythmias and SCD in ATS1 are specific to the type and location of the mutation, so that clinical management should be different for each patient.Altogether, the results may lead to the identification of new molecular targets in the future design of drugs to treat a human disease that currently has no defined therapy.