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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

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