Estudio de la regulación génica en el locus SCN5A-SCN10A y su implicación en la etiología del Síndrome de Brugada
Brugada syndrome (SBr) is a cardiac electrical disease associated with a high susceptibility to ventricular arrhythmias and sudden cardiac death. Genetic variants in the coding regions of the SCN5A gene, which encodes for the cardiac sodium channel, explain 30% of SBr cases. Similarly, genetic varia...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/688715 |
| Acceso en línea: | http://hdl.handle.net/10803/688715 |
| Access Level: | acceso abierto |
| Palabra clave: | Síndrome de Brugada Brugada syndrome Variants genètiques Variantes genéticas Genetic variants Variants no codificants Variantes no codificantes Non-coding variant Locus SCN5A-SCN10A SCN5A-SCN10A locus Regulació de l'expressió gènica Regulación de la expresión génica Gene expression regulation 575 616.1 |
| Sumario: | Brugada syndrome (SBr) is a cardiac electrical disease associated with a high susceptibility to ventricular arrhythmias and sudden cardiac death. Genetic variants in the coding regions of the SCN5A gene, which encodes for the cardiac sodium channel, explain 30% of SBr cases. Similarly, genetic variants in the coding regions of other genes, such as those that encode for the β regulatory subunits of the cardiac sodium channel, calcium channels, or other accessory proteins, explain 5% of SBr cases. In total, coding variants affecting ion channel genes, as well as their regulatory subunits, explain 30-35% of SBr cases. Therefore, in a high proportion of patients diagnosed with SBr, the etiology of the disease remains unknown. Studies carried out over the last decade have shown that the SCN5A-SCN10A locus plays a fundamental role in the control of the transcriptional activity of the SCN5A gene, in addition to being associated with alterations in electrocardiographic parameters, suggesting a relevant role in conduction and heart function. All interacting regulatory components at the locus are required for proper SCN5A expression and cardiac conduction. This evidence suggests that an alteration in the activity of the transcription factors (FT) that regulate the transcription of SCN5A, or the presence of variants in these regions, could induce alterations in cardiac conduction. In this regard, previous studies by the group: (1) revealed the association of a haplotype formed by seven SNVs at the SCN5A-SCN10A locus with SBr by sequencing the regulatory regions of a cohort of 86 individuals with SBr; and (2) identified FT GATA4 as a transcriptional regulator of the SCN5A gene. In addition, preliminary laboratory studies demonstrated that GATA4 acetylation modulates its function as a transcriptional activator of the SCN5A promoter. Based on these observations, our objectives were focused on: (1) understanding in depth the molecular mechanisms that regulate the transcription of SCN5A; (2) identify potential regulatory variants that may alter SCN5A transcription; and (3) relate these factors with possible alterations in sodium currents and arrhythmias |
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