Transcriptional profiling of ion channel genes in Brugada syndrome and other right ventricular arrhythmogenic diseases.

Abstract

AIMS:

Brugada syndrome is an inherited sudden-death arrhythmia syndrome. Na(+)-current dysfunction is central, but mutations in the SCN5A gene (encoding the cardiac Na(+)-channel Nav1.5) are present in only 20% of probands. This study addressed the possibility that Brugada patients display specific expression patterns for ion-channels regulating cardiac conduction, excitability, and repolarization.

METHODS AND RESULTS:

Transcriptional profiling was performed on right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia. Brugada patients showed distinct clustering differences vs. the two control and two other ventricular-tachyarrhythmia groups, including 14 of 77 genes encoding important ion-channel/ion-transporter subunits. Nav1.5 and K(+)-channels Kv4.3 and Kir3.4 were more weakly expressed, whereas the Na(+)-channel Nav2.1 and the K(+)-channel TWIK1 were more strongly expressed, in Brugada syndrome. Differences were also seen in Ca(2+)-homeostasis transcripts, including stronger expression of RYR2 and NCX1. The molecular profile of Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations.

CONCLUSION:

Brugada patients exhibit a common ion-channel molecular expression signature, irrespective of the culprit gene. This finding has potentially important implications for our understanding of the pathophysiology of Brugada syndrome, with possible therapeutic and diagnostic consequences.

• Authors: Nathalie Gaborit, Thomas Wichter, Andras Varro, Viktoria Szuts, Guillaume Lamirault, Lars Eckardt, Matthias Paul, Günter Breithardt, Eric Schulze-Bahr, Denis Escande, Stanley Nattel, Sophie Demolombe
• Journal: European heart journal (Eur Heart J) Vol. 30 Issue 4 Pg. 487-96 (Feb 2009) ISSN: 1522-9645 [Electronic] England
• PMID: 19029124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ion Channels
• Muscle Proteins
• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Sodium Channels

Topics

• Adult
• Arrhythmogenic Right Ventricular Dysplasia (genetics, physiopathology)
• Brugada Syndrome (diagnosis, genetics, physiopathology)
• Female
• Gene Expression
• Gene Expression Profiling (methods)
• Genotype
• Heart Ventricles (metabolism, physiopathology)
• Humans
• Ion Channels (genetics)
• Male
• Middle Aged
• Muscle Proteins (genetics)
• Mutation (genetics)
• NAV1.5 Voltage-Gated Sodium Channel
• Phenotype
• Sodium Channels (genetics)
• Tachycardia, Ventricular (genetics, physiopathology)
• Transcription, Genetic (genetics)
• Young Adult