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

Ueda, Kazuo; Valdivia, Carmen; Medeiros Domingo, Argelia; Tester, David J.; Vatta, Matteo; Farrugia, Gianrico; Ackerman, Michael J.; Makielski, Jonathan C. (2008). Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 105(27), pp. 9355-9360. National Academy of Sciences NAS 10.1073/pnas.0801294105

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Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for approximately 75-80% of cases (LQT1-11). Direct sequencing of SNTA1, the gene encoding alpha1-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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Medeiros Domingo, Argelia


600 Technology > 610 Medicine & health




National Academy of Sciences NAS




Argelia Medeiros Domingo

Date Deposited:

18 Jun 2014 11:52

Last Modified:

05 Dec 2022 14:28

Publisher DOI:


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