α1-Syntrophin variant identified in drug-induced long QT syndrome increases late sodium current

Jongil Choi, Chaojian Wang, Matthew J. Thomas, Geoffrey S. Pitt

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article numbere0152355
JournalPLoS One
Volume11
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

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Long QT Syndrome
Sodium
sodium
drugs
Pharmaceutical Preparations
Cardiac Myocytes
Adenoviridae
cells
syntrophin alpha1
Rats
mutation
Mutation
loci
rats

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

α1-Syntrophin variant identified in drug-induced long QT syndrome increases late sodium current. / Choi, Jongil; Wang, Chaojian; Thomas, Matthew J.; Pitt, Geoffrey S.

In: PLoS One, Vol. 11, No. 3, e0152355, 01.03.2016.

Research output: Contribution to journalArticle

Choi, Jongil ; Wang, Chaojian ; Thomas, Matthew J. ; Pitt, Geoffrey S. / α1-Syntrophin variant identified in drug-induced long QT syndrome increases late sodium current. In: PLoS One. 2016 ; Vol. 11, No. 3.
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