A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness

Kaveh Samani, Geru Wu, Tomohiko Ai, Mossaab Shuraih, Nilesh S. Mathuria, Zhaohui Li, Yoshiro Sohma, Enkhsaikhan Purevjav, Yutao Xi, Jeffrey A. Towbin, Jie Cheng, Matteo Vatta

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1318-1326
Number of pages9
JournalHeart Rhythm
Issue number9
StatePublished - Sep 2009
Externally publishedYes


  • Arrhythmia
  • Brugada syndrome
  • Mutation
  • Severe
  • Sodium channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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