Electrophysiology data for NAA10-R4S-induced pluripotent-derived cardiomyocytes

N-terminal acetyltransferases including NAA10 catalyze N-terminal
acetylation, an evolutionarily conserved co- and post-translational
modification. However, little is known about the role of N-terminal
acetylation in cardiac homeostasis. To gain insight into cardiac-dependent
NAA10 function, we studied a previously unidentified NAA10 variant
p.(Arg4Ser) segregating with QT-prolongation, cardiomyopathy, and
developmental delay in a large kindred. Here, we show that the NAA10R4S
variant reduced enzymatic activity, decreased NAA10-NAA15 complex
formation, and destabilized the enzymatic complex N-terminal
acetyltransferase A. In NAA10R4S/Y-induced pluripotent stem-cell-derived
cardiomyocytes (iPSC-CMs), dysregulation of the late sodium and slow
delayed rectifier potassium currents caused severe repolarization
abnormalities, consistent with clinical QT prolongation. Engineered heart
tissues generated from NAA10R4S/Y-iPSC-CMs had significantly decreased
contractile force and sarcomeric disorganization, consistent with the
pedigree’s cardiomyopathic phenotype. Proteomic studies revealed
dysregulation of metabolic pathways and cardiac structural proteins. We
identified small molecule and genetic therapies that normalized the
phenotype of NAA10R4S/Y-iPSC-CMs. Our study defines the roles of
N-terminal acetylation in cardiac regulation and delineates mechanisms
underlying QT prolongation, arrhythmia, and cardiomyopathy caused by NAA10
dysfunction.