SCN5A variants from a sudden infant death syndrome cohort exhibited defects in sodium channel inactivation, including increased persistent currents (0.5% to 1.7% of peak current).
SCN5A variants identified in SIDS patients exhibit functional defects in sodium channel kinetics and persistent currents, providing biophysical correlates for arrhythmia susceptibility.
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 beta1 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.
“We observed a pattern of SCN5A dysfunction that is reminiscent of what's been observed in LQTS. That gives us confidence that the mutations observed in SIDS victims are not benign genetic variants – but rather could increase the risk of potentially lethal arrhythmias.”
Wang et al. (Tue,) conducted a other in Sudden infant death syndrome (n=201). SCN5A variants vs. Wild-type SCN5A was evaluated on Whole-cell sodium currents (kinetics and voltage dependence of inactivation). SCN5A variants from a sudden infant death syndrome cohort exhibited defects in sodium channel inactivation, including increased persistent currents (0.5% to 1.7% of peak current).