RT Journal Article
T1 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.
A1 Dolz-Gaitón, Pablo
A1 Núñez, Mercedes
A1 Núñez, Lucía
A1 Barana, Adriana
A1 Amorós, Irene
A1 Matamoros, Marcos
A1 Pérez-Hernández, Marta
A1 González de la Fuente, Marta
A1 Alvarez-López, Miguel
A1 Macías-Ruiz, Rosa
A1 Tercedor-Sánchez, Luis
A1 Jiménez-Jáimez, Juan
A1 Delpón, Eva
A1 Caballero, Ricardo
A1 Tamargo, Juan
K1 Síndrome de Brugada
K1 Línea Celular Transformada
K1 Activación del Canal Iónico
K1 Canal de Sodio Activado por Voltaje NAV1.5
K1 Humanos
K1 Arritmias Cardíacas
K1 Análisis Mutacional de ADN
AB INTRODUCTIONWe 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 RESULTSWild-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.CONCLUSIONDespite 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.
PB Public Library of Science
YR 2013
FD 2013-11-25
LK http://hdl.handle.net/10668/1494
UL http://hdl.handle.net/10668/1494
LA en
NO Dolz-Gaitón P, Núñez M, Núñez L, Barana A, Amorós I, Matamoros M, et al. 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. PLoS ONE; 2013, 8(11):e81493
NO Journal Article;
DS RISalud
RD Apr 8, 2025