This Article Full Text 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, G. Articles by Vatta, M. Search for Related Content PubMed Articles by Wu, G. Articles by Vatta, M. Related Collections Arrythmias-basic studies Ion channels/membrane transport Related Article

Original Articles

-1-Syntrophin Mutation and the Long-QT Syndrome

A Disease of Sodium Channel Disruption

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

From the Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, Tex (G.W., T.A., Y.X., S.A., K.S., J.C.); Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, Tex (J.J.K., B.M., Z.L., E.P., J.A.T., M.V.); Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics/Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, Minn (M.J.A.); Heart Research Follow-up Program, University of Rochester Medical Center, Rochester, NY (M.Q., A.J.M.); Division of Cardiology, National Cardiovascular Center, Suita, Japan (W.S.).

Correspondence to Matteo Vatta, PhD, BCM/TCH, 1102 Bates St, F.C. 430.04, Houston, TX 77030. E-mail mvatta{at}bcm.tmc.edu or Tomohiko Ai, MD, PhD, THI/SLEH, 6770 Bertner Ave, MC 2–255, Houston, TX 77030. E-mail tomohikoai@yahoo.com

Received January 28, 2008; accepted May 12, 2008.

Background— Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-₁ (SNTA1) is known to interact with the cardiac sodium channel (hNa_v1.5), and we hypothesized that SNTA1 mutations might cause phenotypic 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 (QTc480 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_v1.5 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_v1.5 similar to the LQT3.

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

---

 

CLINICAL PERSPECTIVE

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCEP.108.769224/DCI.

Presented in part at the 2007 American Heart Association (AHA) Annual Scientific Sessions, Orlando, Fla.

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 Arrhythm Electrophysiol 2008 1: 193-201. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				J. Cheng, D. W. Van Norstrand, A. Medeiros-Domingo, C. Valdivia, B.-h. Tan, B. Ye, S. Kroboth, M. Vatta, D. J. Tester, C. T. January, et al. {alpha}1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current Circ Arrhythm Electrophysiol, December 1, 2009; 2(6): 667 - 676. [Abstract] [Full Text] [PDF]