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

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

“…Biophysical studies of Na channel function have shown that mutations that evoke LQT3 cause excessive Na current (gain-of-function), delaying repolarization and causing early after depolarizations resulting in Torsades de Pointes 13 , whereas Brugada syndrome mutations reduce Na current (loss-of-function), causing premature epicardial repolarization and phase 2 reentry leading to ventricular tachycardia or fibrillation 14 . SCN5A mutations have also been identified in supraventricular arrhythmias such as congenital AV block 15 , sick sinus syndrome (SSS) 12 , and AS 5,6 , but the mechanisms are less well defined as compared with those of ventricular arrhythmias. The present study describes clinical, genetic and biophysical features of the novel SCN5A mutation, L212P, found in a family with congenital progressive AS.…”

“…Several lines of evidence implicate the genetic variations of SCN5A or Cx40 accompanying the SCN5A mutations. Benson et al reported six heterozygous compound SCN5A mutations in three congenital SSS families with recessive inheritance 12 . Affected individuals of one pedigree, who exhibit progressive atrial standstill, exclusively carried heterozygous compound SCN5A mutations of both G1408R and P1298L.…”

“…Genetic screening was performed on three cardiac ion channel genes that have been previously associated with AS, atrial fibrillation, or sick sinus syndrome: the cardiac Na channel SCN5A 6,12 , a component of I f current (hyperpolarization-activated cyclic nucleotide gated, or HCN4) 10 , and Cx40 6 . No mutation was found in HCN4, or in the coding region of Cx40 (exon 2).…”

Mouse models of SCN5A-related cardiac arrhythmias

“…In other families, patients carrying loss-of-function mutations can exhibit symptoms of Brugada syndrome, conduction disease, and sick sinus syndrome, either combined or not (Smits et al, 2005). Severe forms of sick sinus syndrome have also been found in patients with double inheritance of SCN5A loss-of-function mutations (Benson et al, 2003).…”

“…On one hand, gain-of-function mutations, that increase the late component of the Na + current (I Na ) and thus prolong the ventricular action potential, are responsible for the type 3 long QT syndrome (LQT3; Moss and Kass, 2005). On the other hand, loss-of-function mutations decrease I Na and are responsible for cardiac conduction diseases (Schott et al, 1999;Tan et al, 2001;Probst et al, 2003), Brugada syndrome (Gussak et al, 1999), sick sinus syndrome (Benson et al, 2003), and atrial standstill (Groenewegen et al, 2003). To complicate matters further, some SCN5A mutations can lead to more complex diseases associating different phenotypic traits such as, for instance, bradycardia, conduction disease, LQT3, and Brugada syndrome (so-called overlap syndromes; Bezzina et al, 1999;Kyndt et al, 2001;Grant et al, 2002;Rossenbacker et al, 2004;Smits et al, 2005; for review, see Remme et al, 2008).…”