p.D1690N sodium voltage-gated channel α subunit 5 mutation reduced sodium current density and is associated with Brugada syndrome.
Brugada syndrome (BrS) is an inherited primary arrhythmia disorder, leading to sudden cardiac death due to ventricular tachyarrhythmia, but does not exhibit clinical cardiac abnormalities. The sodium voltage-gated channel α subunit 5 (SCN5A) gene, which encodes the α subunit of the cardiac sodium channel, Nav1.5, is the most common pathogenic gene, although ≥22 BrS‑susceptibility genes have previously been identified. In the present study, a novel genetic variant (p.D1690N) localized in the S5‑S6 linker of domain IV of the Nav1.5 channels was identified in a Chinese Han family. Wild‑type (WT) and p.D1690N Nav1.5 channels were transiently over‑expressed in HEK293 cells and analyzed via the whole-cell patch clamp technique. The p.D1690N mutation significantly reduced the peak sodium current density to 23% of WT (at ‑20 mV; P<0.01), shifted steady‑state activation by 7 mV to increasingly positive potentials (P<0.01). Furthermore, prolonging of the recovery from inactivation was observed in the p.D1690N mutant. No significant change was identified in steady‑state inactivation. Thus, the mutant‑induced changes contributed to the loss of function of Nav1.5 channels, which indicates that the p.D1690N variant may have a pathogenic role in BrS.
Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of The Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
Zhipeng
Z
Zeng
Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Qiang
Q
Xie
Key Laboratory of Molecular Biophysics of The Ministry of Education, Cardio‑X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
Yuan
Y
Huang
Key Laboratory of Molecular Biophysics of The Ministry of Education, Cardio‑X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China.
Yuanyuan
Y
Zhao
Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Weihua
W
Li
Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
Zhengrong
Z
Huang
D000328:Adult; D019943:Amino Acid Substitution; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human