Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects

Abstract

Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.

Figure 1. Schematic representation of the structure of the cardiac sodium channel

The locations are indicated where interacting proteins bind to the various regions of the channel. For a number of proteins known to modulate sodium channel function, their putative binding site is unknown. The DI–DIV domains each consist of six transmembrane α-helical segments (S1–S6), which in turn are interconnected by extracellular and cytoplasmic loops. The four domains fold around an ion-conducting pore, which is lined by the extracellular loops (P-loops) between S5 and S6 segments; the P-loops are considered to contain the channels’ selectivity filter for sodium ions (see Kass, 2006). The fourth transmembrane segment, S4, is highly charged and acts as the voltage sensor responsible for increased channel permeability (channel activation) during membrane depolarization (Balser, 2001). The locations are indicated where interacting proteins bind to the various regions of the channel. Redrawn from Shy et al. 2013, with permission.

Figure 2

A, Na_V1.5 resides in distinct macromolecular complexes at two different subcellular domains of the cardiac cell: (top) at the lateral membrane where it interacts with the dystrophin/syntrophin complex; and (bottom) at the intercalated discs with the MAGUK protein SAP97 (reproduced from Shy et al. 2013, with permission). B–E, macropatch measurements in rat ventricular myocytes reveal significant differences in peak sodium current magnitude (B), steady-state activation (C), steady-state inactivation (D) and reactivation (E) between the intercalated disc region (ICD) and the lateral side (Mid) of the cell (reproduced from Lin et al. 2011, with permission).

Figure 3

Potential mechanisms and processes involved in development of cardiac structural abnormalities secondary to SCN5A mutations.

Figure 4

A, variable disease severity in SCN5A-1795insD mutation carriers as demonstrated by a large variation in ECG parameters (upper limit of normal values is indicated by dashed lines). B, spectrum of conduction disease severity among F2-MUT, F1-MUT, 129P2-WT, 129P2-MUT, FVB/NJ-WT and FVB/NJ-MUT mice. WT, wild-type; MUT, Scn5a^1798insD/+. Reproduced in part from Bezzina et al. 1999 and Scicluna et al. 2011, with permission.