PNAS Nexus. 2025 Dec 8;4(12):pgaf379. doi: 10.1093/pnasnexus/pgaf379. eCollection 2025 Dec.
ABSTRACT
Long QT syndrome type 3 (LQTS3), caused by gain-of-function mutations in the SCN5A gene, encompasses a spectrum of clinical presentations, ranging from asymptomatic carriers to severe arrhythmic phenotypes, representing the "silent killer" and "brutal killer" dichotomy. The p.I239V mutation is associated with mild symptoms and minimal arrhythmic events, whereas the newly identified p.M1487K mutation is linked to life-threatening arrhythmic storms. This study aimed to explore the electrophysiological properties of these mutations and their responses to sodium channel blockers to advance precision medicine in LQTS3 management. Genetic analysis identified rare SCN5A mutations in two LQTS3 patients. Site-directed mutagenesis was used to construct mutant SCN5A plasmids, which were expressed in HEK293 cells. Electrophysiological properties were analyzed using patch-clamp techniques, and pharmacological responses to flecainide, mexiletine, and ranolazine were evaluated. Electrophysiological recordings correlated with clinical presentations. Both mutations showed increased window I and faster recovery from inactivation. The p.I239V mutation lacked sustained I, while p.M1487K exhibited significantly increased sustained I (2.3 ± 2.15%, P < 0.0001). Mexiletine and ranolazine effectively reduced sustained I by 76.15 ± 5.83, and 77.63 ± 9.41%, respectively, outperforming flecainide, aligning with clinical responses. This study highlights the role of sustained I in LQTS3 severity and underscores the importance of mutation-specific treatments. By tailoring treatments to the electrophysiological characteristics of each mutation, precision medicine offers a promising approach to improving patient outcomes in LQTS3.
PMID:41416222 | PMC:PMC12708342 | DOI:10.1093/pnasnexus/pgaf379