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Study of the molecular mechanisms that regulate SCN5A expression

Final Report Summary - SODIUM CHANNEL (Study of the molecular mechanisms that regulate SCN5A expression)

Sudden cardiac death (SCD) is the sudden, unexpected natural death from a cardiac cause that occurs in less than one hour after the onset of symptoms in a person without any previous heart condition. SCD is a major contributor to morbidity and mortality in the Western world, affecting ~800,000 individuals annually and underlying 20% of total mortality.
Brugada Syndrome (BrS) is an inherited cardiac disease characterized by an abnormal electrocardiographic pattern and a high risk of SCD. Approximately 11-24% of BrS cases are caused by mutations in exonic regions of the SCN5A gene, which encodes the alpha subunit of the cardiac voltage-gated sodium channel (NaV1.5). These exonic mutations have been associated with NaV1.5 loss-of-function, leading to an alteration of the cardiac action potential. In addition, mutations in exonic regions of other ion channel genes, such as sodium channel regulatory beta subunits and calcium channels, have been linked to another 10-15% of BrS cases. Together, exonic mutations account for up to 25-30% of BrS cases, but the cause of 70-75% of BrS diagnosed patients still remain unknown (‘orphan’ BrS cases).
Based on the hypothesis that altered SCN5A gene expression could increase susceptibility to BrS, in this proposal I aimed to further understand molecular mechanisms that regulate SCN5A expression, and how alterations of these mechanisms could potentially contribute to the development of cardiac arrhythmias such as BrS. As part of the project, we have identified a novel mechanism of transcriptional regulation of the SCN5A gene in the human heart. In addition, we have examined the post-transcriptional regulation of the SCN5A gene by microRNAs, and the physiological relevance of arginine methylation of the cardiac sodium channel NaV1.5. Finally, we have developed a novel strategy to identify potential pathogenic mutations at cis-regulatory regions of BrS-associated genes in currently ‘orphan’ cases of BrS. In summary, with the Sodium Channel IRG project, we have uncovered novel molecular mechanisms in the regulation of the cardiac sodium channel, thereby opening new research lines in the field of cardiac diseases. I predict that the acquired knowledge and our novel developed strategy will have a sound impact for diagnostic or therapeutic purposes in BrS and other arrhythmogenic diseases.
This IRG grant has strongly supported my reintegration at the University of Girona, Spain, after returning from my previous postdoctoral stay at the Gladstone Institutes (UCSF, United States). In 2012, I successfully obtained a “Ramón y Cajal” position, as part of a competitive program of scientific excellence created by the Spanish government to promote reintegration of scientists to the Spanish system. Since then, I have obtained funding to start my own research lines of investigation. I am currently directing two PhD theses, in addition to Master’s thesis and Final Degree Projects. As part of the Medical Sciences Department, I also teach several courses to medical students as well as biomedical master students. I am actively involved in seminar organization and science dissemination.