SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.
BACKGROUND
We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenegre syndrome), long-QT syndrome (LQT3), and Brugada syndrome.


RESULTS
Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III.


CONCLUSIONS
Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.
University of Colorado Cardiovascular Institute, Denver, Colo, USA.
William P
WP
McNair
Lisa
L
Ku
Matthew R G
MR
Taylor
Pam R
PR
Fain
Dmi
D
Dao
Eugene
E
Wolfel
Luisa
L
Mestroni
D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D017354:Point Mutation; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels