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Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

ABSTRACT: Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.

SUBMITTER: Benson DW

PROVIDER: S-EPMC198523 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

Benson D Woodrow DW Wang Dao W DW Dyment Macaira M Knilans Timothy K TK Fish Frank A FA Strieper Margaret J MJ Rhodes Thomas H TH George Alfred L AL

The Journal of clinical investigation 20031001 7

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the al ...[more]

PMID: 14523039

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Project description:RationaleFamilial sick sinus syndrome (SSS) has been linked to loss-of-function mutations of the SCN5A gene, which result in decreased inward Na(+) current, I(Na). However, the functional role of I(Na) in cardiac pacemaking is controversial, and mechanistic links between mutations and sinus node dysfunction in SSS are unclear.ObjectiveTo determine mechanisms by which the SCN5A mutations impair cardiac pacemaking.Methods and resultsAction potential (AP) models for rabbit sinoatrial node (SAN) cells were modified to incorporate experimentally reported I(Na) changes induced by 2 groups of SCN5A gene mutations (affecting the activation and inactivation of I(Na), respectively). The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Effects of the mutations and vagal nerve activity on cardiac pacemaking at the single-cell and tissue levels were studied. Multielectrode extracellular potential recordings of activation pattern from intact SAN-atrium preparations were performed to test predictions of the models. At the single-cell level, the mutations slowed down pacemaking rates in peripheral, but not in central SAN cells that control the heart rhythm. However, in tissue simulations, the mutations not only slowed down pacemaking, but also compromised AP conduction across the SAN-atrium, leading to a possible SAN exit block or sinus arrest, the major features of SSS. Simulated vagal nerve activity amplified the bradycardiac effects of the mutations. Two groups of SCN5A mutations showed subtle differences in impairing the ability of the SAN to drive the surrounding atrium, primarily attributable to their differential effects on atrial excitability and conduction safety. Experimental data with tetrodotoxin and carbachol confirmed the simulation outcomes.ConclusionsOur study substantiates the causative link between SCN5A gene mutations and SSS and illustrates mechanisms by which the mutations impair the driving ability of the SAN.

Dataset Information

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

Publications

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

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