Introduction:
Voltage-gated Na+ channels are crucial for the
amplitude and upstroke of cardiac action potentials (AP), which are
important determinants for driving AP propagation and conduction
velocity throughout the working myocardium1. Mutations
in SCN5A , the gene that encodes Nav1.5, the
predominant cardiac Na+ channel, have been implicated
in rare familial forms of cardiac arrhythmias such as type 3 long QT
syndrome (LQT3) , Brugada syndrome (BS ), progressive
cardiac conduction disorder (PCCD ), atrial fibrillation (AFib),
and sudden infant death syndrome (SIDS) . Another SCN5Amutation has recently been reported to be involved in dilated
cardiomyopathy, a structural heart disease2,3. In
addition to their role in changing gating characteristics, there is
growing recognition that such mutations may also be associated with
alterations in channel protein trafficking and expression levels. SCN5A
gene is also the only gene to have a definitive evidence, for clinical
validity of BS4.
Long QT syndrome (LQTS) is an inherited cardiac channelopathy that may
lead to syncope and even sudden cardiac death as a result of polymorphic
ventricular tachycardia known as torsade de pointes. LQTS manifests as a
prolonged corrected QT (QTc) interval exceeding 450 ms on 12-lead
electrocardiograms (ECG). To date, seventeen genes have been linked to
inherited LQTS but only three have shown a definitive evidence as a
genetic cause for typical LQTS. Those genes are KCNQ1, KCNH2 and
SCN5A5.
LQT3 is caused by mutations in SCN5A genes mapped to chromosome
3q21-24, which encodes the α-subunits of the cardiac
Na+ channel6,7. SCN5Amutations have been identified in about 10% of genotyped LQTS
patients8. When a patient presents a LQTS, a genetic
testing is used to identify the gene that cause the disease. If the gene
is identified, then the clinician knows the type of LQTS (LQT1, LQT2 or
LQT3)9. The development of arrhythmias is often
associated with bradycardia during sleep or relaxation, when the QTc
interval is prolonged. The most common mechanism for QT interval
prolongation in LQT3 is due to a persistent or a late
Na+ current leading to an increase in AP plateau
duration6. This can be a substrate for early after
depolarizations (EADs), which can potentially trigger ventricular
tachyarrhythmias. Most mutations linked to LQT3 are located in exons 23,
26, and 28, which encode the III-IV linker or inactivation gate, the
voltage sensor domain, and the C-terminus of the Na+channel, all of which are involved in fast inactivation. These mutations
impede the proper closure of the channel during this critical process,
resulting in an increase in the number of channels that are unable to
reach a stable inactivated state. This leads to a rise in persistent
Na+ currents unlike the normal inactivation of WT
Na+ channels.
Although SIDS is the leading cause of death in the first year of life,
its cause is still unknown. The only recommended preventive measure is
to avoid placing infants on their stomachs or sides for
sleep10. Several studies have linked SIDS to
LQTS11 and have shown that 50% of infants who die of
SIDS have a prolonged QTc interval and that a prolonged QTc interval
over 440 ms in the first week of life increases the risk of SIDS by a
factor of 4112,13.
We report here on two infants who presented with a prolonged QTc
interval and who died suddenly, most likely after experiencing
ventricular fibrillation. Although the 5- and 12-week-old infants were
within the age range during which the incidence of SIDS peaks, their
deaths were not attributed to SIDS. A sequencing analysis revealed a
heterozygous G‐to‐T base substitution at position 4473 in exon 23 that
resulted in a glutamate (E)‐to‐histidine (H) substitution at residue
1491 and a heterozygous G‐to‐T base substitution at position 4442 in
exon 23 that resulted in a glycine (G)‐to‐valine (V) substitution at
residue 1481. We recorded macroscopic Na+ currents in
transfected mammalian cells using the whole-cell configuration of the
patch-clamp technique. The data revealed a marked shift of inactivation
to more positive potentials, the presence of a persistent
Na+ current, and a large increase in the window
current. All these characteristics point toward a gain-of-function due
to the mutations.