Open AccessFunctional Analysis of SCN5A Genetic Variants Associated with Brugada Syndrome
Author(s) -
В. Б. Михайлова,
Alexey V. Karpushev,
Viola D Vavilova,
Ekaterina Klimenko,
Т. Э. Тулинцева,
Y. Yudina,
Е. С. Васичкина,
Boris S. Zhorov,
Anna Kostareva
Publication year - 2021
Publication title -
cardiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.547
H-Index - 63
eISSN - 1421-9751
pISSN - 0008-6312
DOI - 10.1159/000519857
Subject(s) - brugada syndrome , sodium channel , nav1.5 , electrophysiology , heterologous expression , voltage clamp , western blot , patch clamp , mutation , biology , genetics , chemistry , sodium , microbiology and biotechnology , medicine , gene , recombinant dna , organic chemistry
Background: Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia with increased risk of sudden cardiac death. Mutations in gene SCN5A , which encodes the α-subunit of cardiac voltage-gated sodium channel Na V 1.5, have been identified in over 20% of patients with BrS. However, only a small fraction of Na V 1.5 variants, which are associated with BrS, are characterized in electrophysiological experiments. Results: Here we explored variants V281A and L1582P, which were found in our patients with BrS, and variants F543L and K1419E, which are reportedly associated with BrS. Heterologous expression of the variants in CHO-K1 cells and the Western blot analysis demonstrated that each variant appeared at the cell surface. We further measured sodium current in the whole-cell voltage clamp configuration. Variant F543L produced robust sodium current with a hyperpolarizing shift in the voltage dependence of steady-state fast inactivation. Other variants did not produce detectable sodium currents, indicating a complete loss of function. In a recent cryoEM structure of the hNa V 1.5 channel, residues V281, K1419, and L1582 are in close contacts with residues whose mutations are reportedly associated with BrS, indicating functional importance of respective contacts. Conclusions: Our results support the notion that loss of function of Na V 1.5 or decrease of the channel activity is involved in the pathogenesis of BrS.