Po-01-216 alterations of sialylation machinery in peripheral blood of brugada syndrome patients

Brugada syndrome (BrS) is an inherited arrhythmogenic disease with an increased risk of sudden cardiac death. BrS is considered a genetic disorder, and recent evidence suggests that it should be considered as an oligogenic condition. Mutations are mainly related to the most the SCN5A gene, encoding the alpha subunit of the voltage-gated cardiac sodium channel (NaV1.5). and usually lead to impairment of NaV1.5 functionality, which is still considered the main mechanism of the disease. However, SCN5A mutations are responsible for only 30% of BrS cases. Therefore, it is conceivable that other mechanisms such as post-translational modifications (PTMs) affect NaV1.5 activity. Among others, sialylation may alter ion channel activity by carrying a sugar with a negative charge. Alterations in sialylation have been described in several cardiovascular diseases, as myocardial infarction, Chagas disease, and congenital disorders of glycosylation. The aim was to investigate changes in sialylation in BrS patients to obtain new information on the pathogenesis of BrS. Protein sialylation status of peripheral blood mononuclear cells (PBMCs) BrS patients and healthy controls was assessed with SNA lectin, a sialic acid-binding protein, by Western blot and flow cytometry. Gene expression of enzymes involved in the sialic acid pathway was also examined. NaV1.5 activity and was analyzed with patch clamp technique. The results showed a significant decrease in intracellular and extracellular protein sialylation levels in BrS PBMCs compared with controls. In addition, changes in gene expression of enzymes involved in the sialic acid pathway were detected. These changes correlated with clinical parameters associated with phenotypic expression of the disease, such as arrhythmogenic BrS substrate area. Moreover, protein desialylation caused a reduction of sodium current in an in vitro NaV1.5-overexpressing model, due to sodium channel internalization. These findings support that BrS should be considered a systemic disease and are consistent with the presence of overlapping non-cardiac pathologies, as epilepsy, skeletal muscle channelopathies, and laminopathies in BrS patients. Moreover, the discovery that molecular alterations can be found in the peripheral blood of BrS patients supports the existence of a biomarker of the disease. It is a challenge to develop an effective diagnostic test to screen broadly for BrS.