title: α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.|Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Medical Center, Seoul, Republic of Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Genetics, Department of Pediatrics, University of Virginia Health System, Charlottesville, VA, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C091825:syntrophin alpha1; D012964:Sodium