A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness.
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 hNa(v)1.5 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 degrees C and 40 degrees C.


RESULTS
At 22 degrees 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 degrees C, 37 degrees C and 40 degrees C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40 degrees C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40 degrees C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane.


CONCLUSIONS
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.
Samani
Kaveh
K
Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas 77030, USA.
Wu
Geru
G
Ai
Tomohiko
T
Shuraih
Mossaab
M
Mathuria
Nilesh S
NS
Li
Zhaohui
Z
Sohma
Yoshiro
Y
Purevjav
Enkhsaikhan
E
Xi
Yutao
Y
Towbin
Jeffrey A
JA
Cheng
Jie
J
Vatta
Matteo
M
D000328:Adult; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000235:genetics; D053840:Brugada Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005334:Fever; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels