Published Online
on September 12, 2009

This Article Full Text (PDF) Data Supplement 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 Cheng, J. Articles by Ackerman, M. J. PubMed Articles by Cheng, J. Articles by Ackerman, M. J. Related Collections Arrhythmias, clinical electrophysiology, drugs Pediatric and congenital heart disease, including cardiovascular surgery Genetics of cardiovascular disease Clinical genetics Arrythmias-basic studies

Original Research Article

1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Jianding Cheng¹; David W. Van Norstrand²; Argelia Medeiros–Domingo²; Carmen Valdivia¹; Bi–hua Tan¹; Bin Ye¹; Stacie Kroboth¹; Matteo Vatta³; David J. Tester²; Craig T. January¹; Jonathan C. Makielski¹ and Michael J. Ackerman^2,4

¹ University of Wisconsin, Madison, WI;
² Mayo Clinic, Rochester, MN;
³ Texas Children's Hospital & Baylor College of Medicine, Houston, TX

^* Corresponding author; email: ackerman.michael{at}mayo.edu

Background—Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5%-10% of SIDS may stem from cardiac channelopathies like long QT syndrome (LQTS). We recently implicated mutations in 1-syntrophin (SNTA1) as a novel cause of LQTS, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase (nNOS) by the plasma membrane Ca-ATPase PMCA4b causing increased peak and late sodium current (I_Na) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations.

Methods and Results—Using PCR, DHPLC, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M and G460S) were identified in 8 (~3%) out of 292 SIDS cases. These mutations were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A, nNOS and PMCA4b in HEK293 cells. I_Na was recorded using the whole-cell method. A significant 1.4-1.5 fold increase in peak I_Na and 2.3-2.7 fold increase in late I_Na compared with controls was evident for S287R-, T372M-, and G460S-SNTA1, and was reversed by an nNOS inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation thereby increasing the overlap of the activation and inactivation curves to increase window current.

Conclusions—Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins like 1-syntrophin from similarly rare but innocuous ones.

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