Abstract 12364: Dysfunction of N-terminal Acetylation Causes Multiple Electrical Abnormalities Leading to Long QT Syndrome and Dilated Cardiomyopathy

Abstract

Introduction: NAA10-related syndrome, also known as Ogden syndrome, is characterized by long QT syndrome (LQTS), cardiomyopathy, hypotonia, and neurodevelopmental delay. NAA10 complexes with the regulatory subunit NAA15 to make the post-translationally modifying N-terminal acetyltransferase, NatA. Despite the association of LQTS and NAA10 mutations, the mechanism is unknown. Hypothesis: NAA10 dysfunction affects the function of cardiac ion channels or related proteins causing LQTS. Methods: Target sequencing of large kindred with multiple family members who had LQTS and sudden death revealed a segregating mutation in NAA10 (c.10C>A; p.R4S). Somatic cell reprogramming was used to create an induced pluripotent stem cell (iPSC) line from a gene-positive male patient with LQTS and dilated cardiomyopathy, (pNAA10 R4S ). We also genome-edited the mutation into a control iPSC line (eNAA10 R4S ). The iPSC lines were differentiated into cardiomyocytes (iPSC-CMs) for electrophysiologic characterization. Results: Action potential duration (APD) of wild-type (WT) and mutant iPSC-CMs was evaluated using patch-clamp and dynamic-clamp electrophysiology. There was significant APD prolongation in NAA10 R4S -iPSC-CMs and eNAA10 R4S -iPSC-CMs as compared to WT iPSC-CMs (448.1 ± 102.2 ms and 392.3 ± 20.8 ms, vs 73.1 ± 12.1 ms; p<0.05). We then investigated potential derangements in the underlying sodium (I Na ), potassium (I K ) and calcium (I CaL ) currents. Voltage-clamp measurements demonstrated increased peak I Na in mutant iPSC-CMs lines (pNAA10 R4S : -72.2 ± 11.1 pA/pF and eNAA10 R4S : -77.4 ± 15.3 pA/pF vs. WT: -44.4 ± 7.9 pA/pF, N>12, p<0.05) However, there were no changes in voltage-dependent activation or inactivation. Similarly peak I CaL was also increased (-10.2 ± 1.7 pA/pF, vs -7.0 ± 1.2 pA/pF (N= 5 and 3, respectively)) compared to control iPSC-CMs without any changes in Ca 2+ channel biophysics. There were no significant differences in measured I K . Conclusion: We demonstrate that the NAA10 mutation cause APD prolongation by increasing I Na and I CaL current densities leading to QT prolongation and arrhythmia. This data indicated a novel role for N-terminal acetylation in cardiac ion channel regulation leading to cardiovascular disorders.