IP: Diego Franco Jaime

Resumen del proyecto: Cardiac arrhythmias are physiopathological conditions with a high incidence on the general population, which results in high morbid-mortality rates. Most arrhythmogenic syndromes are caused by functional alteration of ion channel, being therefore referred as “channelopathies”. Currently, the underlying genetic bases of these arrythmogenic processes are limited. In this context, Brugada syndrome (BrS) is an autosomic dominant cardiac disease characterized chronic ventricular arrhythmias (ventricular polymorphic tachycardia and/or ventricular fibrillation) in the absence of structural cardiac abnormalities, which can lead in many cases to sudden cardiac death. At present, point mutations in three different genes (SCN5A, SCN1B and GPD1L) have been associated with this syndrome. However, only 30% of the BrS described cases are caused by mutations in coding sequences of these genes; 95% of which are on SCN5A. On the other hand, there is scarce information regarding the genetic bases of atrial fibrillation (AF), although a genome-wide association study has recently linked genetic variants close to the homeobox transcription factor PITX2 to AF. Our Cardiovascular Development Research group (Department of Experimental Biology, University of Jaén) in collaboration with Dr. Amel Haj Khelil (Biotechnology Institute of Monastir, Tunisia), is interested on dissecting the genetic bases of BrS. For this reason, we have investigated t he molecular abnormalities in these genes in two Tunisian families with BrS, including therein the analyses of the non-coding sequences (3’UTR) and their associated microRNAs. One of the studied families presents a new non synonymous mutation in the SCN5A coding sequence, while the other one only presents molecular defects in the non coding regions as well as on several microRNA precursors. This data suggest therefore that abnormal expression and /or function of these microRNAs could be affecting the expression/function of this cardiac sodium channel, providing a new pathway on the generation/transmission of BrS. Furthermore, we are exploring in our laboratory the functional role of the homeobox transcription factor Pitx2 during cardiac development, using conditional loss-of-function strategies in mice, and dissecting the role of Pitx2 on the AF onset. In this context, we have identified a battery of Pitx2-regulated microRNAs which might be determinant on the AF onset. In this project, we aim to scan putative microRNA mutations associated with cardiac arrhythmias. We have identified a set of microRNAs (20-25) highly expressed in the heart which might play modulatory roles on distinct ion channel expression. Our goal is to perform a comparative analyses using BrS patients (group 1), AF patients (group 2) and a control cohort (groupo 3). We therefore ask to the DNA National Bank to provide us with DNA samples of two cohorts; AF patients (group 2) and control (group 3), since we already have the BrS cohort in our laboratory (group 1).

Entidad financiadora: Junta de Andalucía