alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.

Geru Wu, Tomohiko Ai, Jeffrey J. Kim, Bhagyalaxmi Mohapatra, Yutao Xi, Zhaohui Li, Shahrzad Abbasi, Enkhsaikhan Purevjav, Kaveh Samani, Michael J. Ackerman, Ming Qi, Arthur J. Moss, Wataru Shimizu, Jeffrey A. Towbin, Jie Cheng, Matteo Vatta

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


BACKGROUND: Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.5 by secondarily disturbing sodium channel function. METHODS AND RESULTS: Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc> or =480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa(v)1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V(h)) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. CONCLUSION: SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3.

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalCirculation. Arrhythmia and electrophysiology
Issue number3
StatePublished - Aug 2008
Externally publishedYes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


Dive into the research topics of 'alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.'. Together they form a unique fingerprint.

Cite this