TY - JOUR
T1 - A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness
AU - Samani, Kaveh
AU - Wu, Geru
AU - Ai, Tomohiko
AU - Shuraih, Mossaab
AU - Mathuria, Nilesh S.
AU - Li, Zhaohui
AU - Sohma, Yoshiro
AU - Purevjav, Enkhsaikhan
AU - Xi, Yutao
AU - Towbin, Jeffrey A.
AU - Cheng, Jie
AU - Vatta, Matteo
PY - 2009/9
Y1 - 2009/9
N2 - Background: Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been implicated in the pathogenesis of Brugada syndrome (BrS). Febrile illnesses have been recognized to unmask and/or trigger the BrS phenotype. However, the pathophysiological mechanism has not been fully elucidated. Objective: A novel SCN5A missense mutation, V1340I, was identified in a patient with BrS suffering from frequent episodes of polymorphic ventricular tachycardia (VT) and syncope associated with fever. The biophysical modifications of hNav1.5 by V1340I were studied. Methods: The effects of the V1340I mutation were studied in the 2 splice variants, SCN5A and SCN5A-Q1077del (delQ), using patch-clamp techniques at various temperatures between 22°C and 40°C. Results: At 22°C, V1340I-SCN5A generated markedly diminished sodium currents compared to the wild-type (WT) SCN5A. On the contrary, V1340I-delQ generated almost identical current density compared to the WT-delQ. However, V1340I-delQ significantly attenuated the peak current density compared to the WT-delQ at 32°C, 37°C and 40°C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40°C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40°C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane. Conclusion: Our study supports the concept that febrile illness predisposes individuals who carry a loss of function SCN5A mutation, such as V1340I, to fever-induced ventricular arrhythmias in BrS by significantly reducing the sodium currents in the hyperthermic state.
AB - Background: Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been implicated in the pathogenesis of Brugada syndrome (BrS). Febrile illnesses have been recognized to unmask and/or trigger the BrS phenotype. However, the pathophysiological mechanism has not been fully elucidated. Objective: A novel SCN5A missense mutation, V1340I, was identified in a patient with BrS suffering from frequent episodes of polymorphic ventricular tachycardia (VT) and syncope associated with fever. The biophysical modifications of hNav1.5 by V1340I were studied. Methods: The effects of the V1340I mutation were studied in the 2 splice variants, SCN5A and SCN5A-Q1077del (delQ), using patch-clamp techniques at various temperatures between 22°C and 40°C. Results: At 22°C, V1340I-SCN5A generated markedly diminished sodium currents compared to the wild-type (WT) SCN5A. On the contrary, V1340I-delQ generated almost identical current density compared to the WT-delQ. However, V1340I-delQ significantly attenuated the peak current density compared to the WT-delQ at 32°C, 37°C and 40°C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40°C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40°C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane. Conclusion: Our study supports the concept that febrile illness predisposes individuals who carry a loss of function SCN5A mutation, such as V1340I, to fever-induced ventricular arrhythmias in BrS by significantly reducing the sodium currents in the hyperthermic state.
KW - Arrhythmia
KW - Brugada syndrome
KW - Mutation
KW - Severe
KW - Sodium channel
UR - http://www.scopus.com/inward/record.url?scp=68949219422&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68949219422&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2009.05.016
DO - 10.1016/j.hrthm.2009.05.016
M3 - Article
C2 - 19648062
AN - SCOPUS:68949219422
SN - 1547-5271
VL - 6
SP - 1318
EP - 1326
JO - Heart Rhythm
JF - Heart Rhythm
IS - 9
ER -