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
![Thumbnail](/xmlui/themes/Mirage2//images/thumbnails/thumn_cientif.png)
Identificadores![](/xmlui/themes/Mirage2//images/despl_identif.png)
Identificadores
Visualización o descarga de ficheros![](/xmlui/themes/Mirage2//images/despl_contenidos.png)
Visualización o descarga de ficheros
Fecha de publicación
2013Título de revista
PLoS One
Tipo de contenido
Artigo
DeCS
Transporte Biológico | Síndrome de Brugada | Mutación del Sistema de Lectura | Canal de Sodio Activado por Voltaje NAV1.5MeSH
Biological Transport | Brugada Syndrome | Frameshift Mutation | NAV1.5 Voltage-Gated Sodium ChannelResumen
Introduction: We functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) found in a proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry the mutation and showed a Brugada syndrome with an incomplete and variable expression. The mutation (p.D1816VfsX7) resulted in a severe truncation (201 residues) of the Nav1.5 C-terminus.
Methods and results: Wild-type (WT) and mutated Nav1.5 channels together with hNavβ1 were expressed in CHO cells and currents were recorded at room temperature using the whole-cell patch-clamp. Expression of p.D1816VfsX7 alone resulted in a marked reduction (≈90%) in peak Na(+) current density compared with WT channels. Peak current density generated by p.D1816VfsX7+WT was ≈50% of that generated by WT channels. p.D1816VfsX7 positively shifted activation and inactivation curves, leading to a significant reduction of the window current. The mutation accelerated current activation and reactivation kinetics and increased the fraction of channels developing slow inactivation with prolonged depolarizations. However, late INa was not modified by the mutation. p.D1816VfsX7 produced a marked reduction of channel trafficking toward the membrane that was not restored by decreasing incubation temperature during cell culture or by incubation with 300 μM mexiletine and 5 mM 4-phenylbutirate.
Conclusion: Despite a severe truncation of the C-terminus, the resulting mutated channels generate currents, albeit with reduced amplitude and altered biophysical properties, confirming the key role of the C-terminal domain in the expression and function of the cardiac Na(+) channel.
![](/xmlui/themes/Mirage2//images/final_lines.png)