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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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Syntrophin mutation and late sodium current.A schematic diagram shows variants in SNTA1 lead to disrupted binding to PMCA4b and released inhibition of nNOS, resulting in increased INa-L through S-nitrosylation of NaV1.5.
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pone.0152355.g006: Syntrophin mutation and late sodium current.A schematic diagram shows variants in SNTA1 lead to disrupted binding to PMCA4b and released inhibition of nNOS, resulting in increased INa-L through S-nitrosylation of NaV1.5.

Mentions: SNTA1 is now a well-established a NaV1.5 channel interacting protein (NaChIP) in complex with nNOS and PMCA4b.[31] Mutations lead to gain-of-function modulations of NaV1.5 (increased INa-L) and cLQTS. Ueda et al. reported a missense mutation (p.A390V) within the PH2 domain of SNTA1 disrupted its binding with PMCA4b, thereby disinhibiting nNOS, which caused S-nitrosylation of NaV1.5 and a resultant increase in INa-L.[16] The novel variant tested here, p.E409Q lies outside of the PH2 domain. Thus, the data showing that p.E409Q affects NaV1.5 currents similarly to p.A390V in both cardiomyocytes, and in a heterologous system in which all the key components of the macromolecular complex are present, suggest that E409Q affects PMCA4b interaction similarly to A390V. We conclude, therefore, that the binding site for PMCA4b must extend further towards the C-terminus on PMCA4b than the PH2 domain or that the E409Q variant affects the PH2 binding domain allosterically. A schematic depicting this proposed interaction and the consequent mechanism for increased INa-L is shown in Fig 6.


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)

Syntrophin mutation and late sodium current.A schematic diagram shows variants in SNTA1 lead to disrupted binding to PMCA4b and released inhibition of nNOS, resulting in increased INa-L through S-nitrosylation of NaV1.5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814026&req=5

pone.0152355.g006: Syntrophin mutation and late sodium current.A schematic diagram shows variants in SNTA1 lead to disrupted binding to PMCA4b and released inhibition of nNOS, resulting in increased INa-L through S-nitrosylation of NaV1.5.
Mentions: SNTA1 is now a well-established a NaV1.5 channel interacting protein (NaChIP) in complex with nNOS and PMCA4b.[31] Mutations lead to gain-of-function modulations of NaV1.5 (increased INa-L) and cLQTS. Ueda et al. reported a missense mutation (p.A390V) within the PH2 domain of SNTA1 disrupted its binding with PMCA4b, thereby disinhibiting nNOS, which caused S-nitrosylation of NaV1.5 and a resultant increase in INa-L.[16] The novel variant tested here, p.E409Q lies outside of the PH2 domain. Thus, the data showing that p.E409Q affects NaV1.5 currents similarly to p.A390V in both cardiomyocytes, and in a heterologous system in which all the key components of the macromolecular complex are present, suggest that E409Q affects PMCA4b interaction similarly to A390V. We conclude, therefore, that the binding site for PMCA4b must extend further towards the C-terminus on PMCA4b than the PH2 domain or that the E409Q variant affects the PH2 binding domain allosterically. A schematic depicting this proposed interaction and the consequent mechanism for increased INa-L is shown in Fig 6.

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