Abstract 16625: Frameshift Mutation in LMNA Gene Causes Atrial Arrhythmogenesis via Epigenetic Inhibition of KCNA5 Expression

Abstract

Introduction: Cardiolaminopathy is a genetic heart disease caused by LMNA mutations, often leading to atrial tachycardia, AV block, ventricular arrhythmia and eventually dilated cardiomyopathy. While performing WES on pedigrees with primary atrial myopathy, we identified that nearly half of them possess mutations on the LMNA gene. However, previous studies on laminopathy have mainly focused on ventricular lesions, leaving the mechanism of how LMNA mutation leads to the atrial myopathy yet to be elucidated. Methods: To better understand the role of the LMNA gene in atrial cardiomyopathy, we employed the CRISPR/Cas9 to establish a heterozygous KI mouse model with a frameshift mutation ( lmna c.1249delA, p.K418Sfs) identified from a pedigree of atrial cardiomyopathy. Results: The heterozygous mice displayed progressive and spontaneous atrial arrhythmia, along with increased fibrosis, without any involvement of the ventricles, which was consistent with the affected individuals in the pedigree. Electrophysiological measurements showed prolonged APD90, an increased occurrence of EAD events, and augmented atrial conduction heterogeneity compared to the control mice. Bioinformatics analysis of mouse atrium indicated KCNA5 , which specifically expressed in the atrium, was significantly down-regulated. This reduction was further corroborated through Western blotting and immunofluorescence. Additionally, ChIP qPCR analysis revealed an enhanced binding of KCNA5 with lamin A/C and reduced binding with the promoting histone H3K4me3 in the mutant atrium. Notably, the presence of atrial arrhythmia and the downregulation of KCNA5 were also observed in another lmna frameshift mutation mouse model, suggesting that these mechanisms may be universal in LMNA -related atrial cardiomyopathy. Conclusions: Laminopathy causing atrial cardiomyopathy has long been underestimated. Our study validates the pathogenicity of LMNA frameshift mutation for the atrium and highlights epigenetic changes leading to KCNA5 expression downregulation and consequential phenotypic alterations. These results broaden the current knowledge of laminopathy beyond its previous emphasis on ventricular lesions, offering potential therapeutic targets for the disease.