Syntrophin mutation associated with long QT syndrome through activation of the nNOS–SCN5A macromolecular complex
K Ueda, C Valdivia… - Proceedings of the …, 2008 - National Acad Sciences
K Ueda, C Valdivia, A Medeiros-Domingo, DJ Tester, M Vatta, G Farrugia, MJ Ackerman…
Proceedings of the National Academy of Sciences, 2008•National Acad SciencesMutations 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 …
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 …
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.
National Acad Sciences