Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Macias, A.; Gonzalez-Guerra, A.; Moreno-Manuel, A. I.; Cruz, F. M.; Garcia-Quintans, N.; Gutierrez, L. K.; Roche-Molina, M.; Bermudez-Jimenez, F. J.; Andres, V.; Vera-Pedrosa, M. L.; Martinez-Carrascoso, I.; Bernal, J. A.; Jalife, J.

doi:10.1101/2021.06.17.448833

bioRxiv · 10.1101/2021.06.17.448833

Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Macias, A.·Gonzalez-Guerra, A.·Moreno-Manuel, A. I.·Cruz, F. M.·Garcia-Quintans, N.·Gutierrez, L. K.·Roche-Molina, M.·Bermudez-Jimenez, F. J.·Andres, V.·Vera-Pedrosa, M. L.·Martinez-Carrascoso, I.·Bernal, J. A.·Jalife, J.

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Abstract

Andersen-Tawil Syndrome (ATS) is associated with life threatening arrhythmias of unknown mechanism. We report on a mouse model carrying the trafficking-deficient mutant Kir2.1{Delta}314-315. The mouse recapitulates the electrophysiological phenotype of type 1 (ATS1), with slower conduction velocities in response to flecainide, QT prolongation exacerbated by isoproterenol, and increased vulnerability to calcium-mediated arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia (CPVT). Kir2.1{Delta}314-315 expression significantly reduced inward rectifier K+ and Na+ inward currents, depolarized resting membrane potential and prolonged action potential duration. Immunolocalization in wildtype cardiomyocytes and skeletal muscle cells revealed a novel sarcoplasmic reticulum (SR) microdomain of functional Kir2.1 channels contributing to intracellular Ca2+ homeostasis. Kir2.1{Delta}314-315 cardiomyocytes showed defects in SR Kir2.1 localization and function, which contributed to abnormal spontaneous Ca2+ release events. This is the first in-vivo demonstration of a dual arrhythmogenic mechanism of ATS1 defects in Kir2.1 channel function at the sarcolemma and the SR, with overlap between ATS1 and CPVT.

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Macias, A., Gonzalez-Guerra, A., Moreno-Manuel, A. I., Cruz, F. M., Garcia-Quintans, N., Gutierrez, L. K., Roche-Molina, M., Bermudez-Jimenez, F. J., Andres, V., Vera-Pedrosa, M. L., Martinez-Carrascoso, I., Bernal, J. A., Jalife, J.. 2021-06-17. Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1. https://doi.org/10.1101/2021.06.17.448833

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