Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex

Kazuo Ueda, Carmen Valdivia, Argelia Medeiros-Domingo, David J. Tester, Matteo Vatta, Gianrico Farrugia, Michael J. Ackerman, Jonathan C. Makielski

Research output: Contribution to journalArticlepeer-review

254 Scopus citations


Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for ≈75-80% of cases (LQT1-11). Direct sequencing of SNTA1, the gene encoding α1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S-nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.

Original languageEnglish (US)
Pages (from-to)9355-9360
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - Jul 8 2008


  • Cardiac arrhythmia
  • Ion channel
  • Nitrosylation
  • Plasma membrane Ca-ATPase
  • Sodium current

ASJC Scopus subject areas

  • General


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