Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics

Abstract

Background— Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel ( SCN5A ), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results— We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A -negative probands (47.0±4.6 years; n=10; P <0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P <0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). Conclusions— The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.

Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome

“…We recently found that familial SSS probands carrying SCN5A mutations showed a significantly earlier disease onset and a strong male predominance, whereas nonfamilial SSS had a disease onset of over 70 years for both sexes, which were affected equally. 22 The affected members of the SSS family in the present study were both women, aged over 60 years, suggesting that familial SSS with MYH6 mutations might constitute an SSS subgroup distinct from that caused by SCN5A mutations. This may suggest the existence of a new disease entity of inherited arrhythmias attributable to mutations in genes encoding sarcomere proteins other than cardiac ion channel or ion channel-associated genes.…”

“…22 We found that the mutant delE933-MYH6 slowed down action potential propagation when heterologously expressed in the atrial myocardial cell line HL-1 ( Figure 4A). Moreover, knockdown of endogenous MYH6 leading to reduced heart rate in zebrafish could be compensated for by the coexpression of WT-MYH6 but not by delE933-MYH6 ( Figure 4B).…”

“…22 In this study, we enrolled 9 SSS families out of this cohort, which were free from SCN5A or HCN4 mutations. Age at diagnosis of the probands (3 male and 6 female) ranged from 3 to 65 years old (44.6±21.8 years old; mean±SD).…”

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy

“…11, 12 To date, SCN5A-D1275N has been reportedly associated with a wide variety of arrhythmias, with or without DCM. 13, 25 Functional studies into the electrophysiology of SCN5A-D1275N channels have reported contradictory results. Some studies using heterologous expression systems such as Xenopus oocytes, Chinese hamster ovary cells, or tsA201 cells, showed no major differences in the peak sodium current densities and sodium channel kinetics of WT and D1275N channels, 14,16 whereas another study using Xenopus oocytes and HEK 293 cells found a reduction in peak sodium current densities in D1275N channels.…”

Asymptomatic Brugada Syndrome

“…Conduction disturbances in BS have been associated with a worst outcome, 18 and relation between SND, sodium channelopathies, and BS is well known. [19][20][21] The mechanism responsible for this is not clear; a more expressive form of the disease might be involved. Specific studies with biggest population and follow-up should be performed to clarify this issue.…”