Published Online
on January 8, 2007

A more recent version of this article appeared on January 23, 2007

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Submitted on June 15, 2006
Accepted on September 1, 2006

Cardiac Sodium Channel Dysfunction in Sudden Infant Death Syndrome

Dao W. Wang MD, Reshma R. Desai MS, Lia Crotti MD, Marianne Arnestad MD, PhD, Roberto Insolia BSc, Matteo Pedrazzini BSc, Chiara Ferrandi BSc, Ashild Vege MD, PhD, Torleiv Rognum MD, PhD, Peter J. Schwartz MD, and Alfred L. George Jr MD^*

From the Departments of Pharmacology (DW.W., A.L.G.) and Medicine (R.R.D., A.L.G.), Vanderbilt University, Nashville, Tenn; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.,), IRCCS Policlinico S. Matteo, Pavia, Italy; Department of Cardiology (L.C., P.J.S.), University of Pavia and IRCCS Policlinico S. Matteo, Pavia, Italy; Institute of Forensic Medicine (M.A., A.V., T.R.), University of Oslo, Oslo, Norway.

^* To whom correspondence should be addressed. E-mail: al.george{at}vanderbilt.edu.

Background--Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several SCN5A variants were identified in a Norwegian sudden infant death syndrome cohort (n=201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts.

Methods and Results--Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant SCN5A cDNA (hH1) coexpressed with the human 1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of SCN5A mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype.

Conclusions--Our present results greatly expand the spectrum of functionally characterized SCN5A variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome.

Key words: death, sudden • genetics • ion channels • long-QT syndrome

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