Published Online
on May 28, 2008

A more recent version of this article appeared on August 1, 2008

This Article Full Text (PDF) All Versions of this Article: 1/3/193    most recent CIRCEP.108.769224v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wu, G. Articles by Vatta, M. PubMed Articles by Wu, G. Articles by Vatta, M. Related Collections Arrythmias-basic studies Ion channels/membrane transport Related Article

Original Article

Alpha-1-Syntrophin Mutation and the Long QT Syndrome: a disease of sodium channel disruption

Geru Wu¹, Tomohiko Ai¹, Jeffrey J. Kim², Bhagyalaxmi Mohapatra², Yutao Xi¹, Zhaohui Li², Shahrzad Abbasi¹, Enkhsaikhan Purevjav², Kaveh Samani¹, Michael J. Ackerman³, Ming Qi⁴, Arthur J. Moss⁴, Wataru Shimizu⁵, Jeffrey A. Towbin², Jie Cheng¹ and Matteo Vatta^2,6

¹ Texas Heart Institute;
² Baylor College of Medicine;
³ Mayo Clinic;
⁴ University of Rochester Medical Center;
⁵ National Cardiovascular Center, Suita, Japan

Correspondence: ⁶ E-mail: mvatta{at}bcm.tmc.edu

Background—Long QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein alpha-1-syntrophin (SNTA1) is known to interact with the cardiac sodium channel (hNa_v1.5) and we hypothesized that SNTA1 mutations might cause phenotypical LQTS in patients with genotypically normal hNa_v1.5 by secondarily disturbing sodium channel function.

Methods and Results—Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc 480ms) 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 one 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_v1.5 and transiently transfected with either wild type (WT) or mutant SNTA1, and in neonatal rat cardiomyocytes transiently expressing with either WT or mutant SNTA1. In both HEK293 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 I-V relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V_h) leftward by 9.4 mV, while the voltage-dependent inactivation kinetics and the late sodium currents were similar to WT-SNTA1.

Conclusion—SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na_v1.5 similar to the LQT3.

Key Words: arrhythmia • death, sudden (if surviving, use heart arrest) • ion channels • long-QT syndrome • SNTA1

Related Article

-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, and Matteo Vatta
Circ Arrhythmia Electrophysiol 2008 1: 193-201. [Abstract] [Full Text] [PDF]