α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current

• Published in: PloS one 2016-03, Vol.11 (3), p.e0152355-e0152355
• Main Authors: Choi, Jong-Il, Wang, Chaojian, Thomas, Matthew J, Pitt, Geoffrey S
• Format: Article
• Language: English
• Subjects: Adenoviruses; Adult; Animals; Biology and Life Sciences; Calcium-Binding Proteins - genetics; Cardiac arrhythmia; Cardiology; Cardiomyocytes; Consent; Electrocardiography; Genetic Association Studies; Genetic Predisposition to Disease; Heart diseases; Heart failure; HEK293 Cells; Humans; Kinases; Long QT syndrome; Long QT Syndrome - genetics; Male; Medicine; Medicine and Health Sciences; Membrane Potentials; Membrane Proteins - genetics; Muscle Proteins - genetics; Mutation; Mutation, Missense; Myocytes, Cardiac - metabolism; Physical Sciences; Plasmids; Proteins; Rats, Sprague-Dawley; Research and Analysis Methods; Sodium; Sodium - metabolism; Sodium channels (voltage-gated); Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152355

Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.