Functional Characterization of a Novel Frameshift Mutation in the C-terminus of the Nav1.5 Channel Underlying a Brugada Syndrome with Variable Expression in a Spanish Family

• DOI: 10.1371/journal.pone.0081493
• Publication Date: 2013-11-26T01:17:15Z
• Authors: Pablo Dolz-Gaitón; Mercedes Núñez; Lucía Núñez; Adriana Barana; Irene Amorós; Marcos Matamoros; Marta Pérez-Herná...; Marta González de...; Miguel Álvarez-López; Rosa Macías-Ruiz; Luis Tercedor-Sán...; Juan Jiménez-Jáimez; Eva Delpón; Ricardo Caballero; Juan Tamargo
• Keywords: Nav1.5

IntroductionWe functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na+ channels (Nav1.5) found proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry showed Brugada syndrome an incomplete variable expression. The (p.D1816VfsX7) resulted severe truncation (201 residues) Nav1.5 C-terminus. Methods ResultsWild-type (WT) mutated together hNavβ1 were expressed CHO cells currents recorded at room temperature using whole-cell patch-clamp. Expression p.D1816VfsX7 alone marked reduction (≈90%) peak current density compared WT channels. Peak generated by p.D1816VfsX7+WT was ≈50% that positively shifted activation inactivation curves, leading to significant window current. accelerated reactivation kinetics increased fraction developing slow prolonged depolarizations. However, late INa not modified mutation. produced channel trafficking toward membrane restored decreasing incubation during cell culture or 300 μM mexiletine 5 mM 4-phenylbutirate. ConclusionDespite C-terminus, resulting generate currents, albeit reduced amplitude altered biophysical properties, confirming key role C-terminal domain expression function channel.