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

Choi JI, Wang C, Thomas MJ, Pitt GS - PLoS ONE (2016)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

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.

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.

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Late Na+ current in adult rat cardiomyocyte infected with adenoviruses expressing either the WT or one of the two SNTA1 mutants.(A) Representative late Na+ currents in with WT and the SNTA1 variants (Fig 5A). (B) E409Q-SNTA1 significantly increased INa-L compared to that of WT-SNTA1. * P<0.05 versus WT-SNTA1. INa indicates sodium current; TTX, tetrodotoxin. Mean and standard error of mean (SEM) are shown in the graph.
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pone.0152355.g005: Late Na+ current in adult rat cardiomyocyte infected with adenoviruses expressing either the WT or one of the two SNTA1 mutants.(A) Representative late Na+ currents in with WT and the SNTA1 variants (Fig 5A). (B) E409Q-SNTA1 significantly increased INa-L compared to that of WT-SNTA1. * P<0.05 versus WT-SNTA1. INa indicates sodium current; TTX, tetrodotoxin. Mean and standard error of mean (SEM) are shown in the graph.

Mentions: The INa-L was measured using a long depolarization pulse (200 ms at -40 mV from a holding potential of -120 mV) and background was subtracted after TTX (30 μM) was applied to the bath. Representative traces are shown in Fig 5A and the data are summarized in Table 2. Compared to WT-STNA1, INa-L (% of peak current) was significantly increased with E409Q mutant, but not the A390V mutant (0.49±0.14 in WT-SNTA1 vs. 0.94±0.23 in A390V-SNTA1, p = 0.099; vs. 1.12±0.24 in E409Q-SNTA1, p = 0.019) (Fig 5B). There was no significant difference in INa-L between A390V-SNTA1 and E409Q-SNTA1 (p = 0.903).


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

Choi JI, Wang C, Thomas MJ, Pitt GS - PLoS ONE (2016)

Late Na+ current in adult rat cardiomyocyte infected with adenoviruses expressing either the WT or one of the two SNTA1 mutants.(A) Representative late Na+ currents in with WT and the SNTA1 variants (Fig 5A). (B) E409Q-SNTA1 significantly increased INa-L compared to that of WT-SNTA1. * P<0.05 versus WT-SNTA1. INa indicates sodium current; TTX, tetrodotoxin. Mean and standard error of mean (SEM) are shown in the graph.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4814026&req=5

pone.0152355.g005: Late Na+ current in adult rat cardiomyocyte infected with adenoviruses expressing either the WT or one of the two SNTA1 mutants.(A) Representative late Na+ currents in with WT and the SNTA1 variants (Fig 5A). (B) E409Q-SNTA1 significantly increased INa-L compared to that of WT-SNTA1. * P<0.05 versus WT-SNTA1. INa indicates sodium current; TTX, tetrodotoxin. Mean and standard error of mean (SEM) are shown in the graph.
Mentions: The INa-L was measured using a long depolarization pulse (200 ms at -40 mV from a holding potential of -120 mV) and background was subtracted after TTX (30 μM) was applied to the bath. Representative traces are shown in Fig 5A and the data are summarized in Table 2. Compared to WT-STNA1, INa-L (% of peak current) was significantly increased with E409Q mutant, but not the A390V mutant (0.49±0.14 in WT-SNTA1 vs. 0.94±0.23 in A390V-SNTA1, p = 0.099; vs. 1.12±0.24 in E409Q-SNTA1, p = 0.019) (Fig 5B). There was no significant difference in INa-L between A390V-SNTA1 and E409Q-SNTA1 (p = 0.903).

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus