Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients

• Main Authors: Cristina Balla, Elena Conte, Rita Selvatici, Renè Massimiliano Marsano, Andrea Gerbino, Marianna Farnè, Rikard Blunck, Francesco Vitali, Annarita Armaroli, Alessandro Brieda, Antonella Liantonio, Annamaria De Luca, Alessandra Ferlini, Claudio Rapezzi, Matteo Bertini, Francesca Gualandi, Paola Imbrici
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: International Journal of Molecular Sciences
• Subjects: Brugada syndrome; <i>SCN5A</i>; electrophysiology; Na⁺ current
• Online Access: https://www.mdpi.com/1422-0067/22/12/6513

Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The <i>SCN5A</i> gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel <i>SCN5A</i> mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.