Molecular basis of abnormal heartbeat
Brugada Syndrome (BrS) is an inherited cardiac disease characterised by an abnormal electrocardiographic pattern and a high risk of sudden cardiac death. Up to 24 % of the cases display mutations in the SCN5A gene, which encodes a subunit of the cardiac voltage-gated sodium channel (NaV1.5). These mutations lead to NaV1.5 loss of function and change the cardiac action potential. Additional mutations in other ion channel genes have been identified but still nearly 70 % of BrS cases have an unknown aetiology. The primary objective of the EU-funded SODIUM CHANNEL (Study of the molecular mechanisms that regulate SCN5A expression) project was to delineate the molecular mechanisms underlying the regulation of SCN5A expression. The working hypothesis was that in a percentage of BrS in which the cause is still unknown, SCN5A expression might be deregulated causing cardiac arrhythmias. Researchers performed chromatin immunoprecipitation (ChIP) analysis of the SCN5A gene in human cardiac tissue. They identified a novel mechanism of transcriptional regulation of the SCN5A gene in the human heart. They unravelled a role for the transcription factor GATA4, which in cooperation with GATA5 enhanced the activity of the SCN5A promoter and induced gene transcription. Additionally, they examined the role of microRNAs in the post-transcriptional regulation of the SCN5A gene and the physiological relevance of arginine methylation of NaV1.5 in human cardiac tissue. Furthermore, they developed a method for the identification of pathogenic mutations in the regulatory regions of the SCN5A gene. Collectively, the efforts of the SODIUM CHANNEL study led to the discovery of novel molecular mechanisms involved in the regulation of the cardiac sodium channel NaV1.5. These results open up new roads for studying cardiac diseases and are envisaged to impact the diagnosis and therapy of BrS and other arrhythmogenic diseases.
Keywords
Brugada Syndrome, sudden cardiac death, mutation, SCN5A, sodium channel NaV1.5, GATA-4
