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

Titleα1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.
Publication TypeJournal Article
Year of Publication2016
AuthorsChoi J-I, Wang C, Thomas MJ, Pitt GS
JournalPLoS One
Date Published2016
KeywordsAdult, Animals, Calcium-Binding Proteins, Genetic Association Studies, Genetic Predisposition to Disease, HEK293 Cells, Humans, Long QT Syndrome, Male, Membrane Potentials, Membrane Proteins, Muscle Proteins, Mutation, Missense, Myocytes, Cardiac, Rats, Sprague-Dawley, Sodium

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.

Alternate JournalPLoS ONE
PubMed ID27028743
PubMed Central IDPMC4814026
Grant ListR01 HL122967 / HL / NHLBI NIH HHS / United States
R01 HL112918 / HL / NHLBI NIH HHS / United States