A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill

Abstract

Abstract-Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides Ϫ44 (G3 A) and ϩ71 (A3 G). Eight relatives were homozygous for both polymorphisms, which occurred in only Ϸ7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS. (Circ Res. 2003;92:14-22.)

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.…”

“…We previously identified a missense mutation R367H in a transient AS case complicated with Brugada syndrome 5 , and the recombinant channel showed total loss of Na current when expressed heterologously. In contrast, another SCN5A mutation, D1275N, found in a small Dutch kindred with progressive AS, showed relatively benign biophysical abnormalities 6 . Moreover, some mutation carriers in this pedigree exhibit a normal electrocardiogram, and further screening of atria-specific genes has demonstrated that the affected individuals exclusively carry both D1275N mutation and homozygous polymorphisms in the regulatory region of connexin 40 (Cx40), supporting an argument favoring digenic inheritance.…”

“…PCR was used to amplify the coding region and flaking intron sequence of SCN5A, as previously described 9 . Exon 1 of Cx40 was amplified as previously reported 6 , and the exon 2 that covers the entire coding region of Cx40 was amplified by using a primer set (Cx40-F2:…”

“…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).…”

“…Moreover, some mutation carriers in this pedigree exhibit a normal electrocardiogram, and further screening of atria-specific genes has demonstrated that the affected individuals exclusively carry both D1275N mutation and homozygous polymorphisms in the regulatory region of connexin 40 (Cx40), supporting an argument favoring digenic inheritance. Cx40 is a gap junction protein predominantly expressed in the atrium and the specialized conduction system, and the single nucleotide polymorphisms (SNPs) result in reduced Cx40 expression in vitro 6 . Furthermore, these SNPs have been clinically associated with enhanced atrial vulnerability and increased risk of atrial fibrillation 7 .…”